Gene Info
Gene(s) annotations
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GET /lookup/gene/TP53/hg19?add-all-data=1&=&format=api
{ "symbol": "TP53", "gene_id": 33956, "description": "tumor protein p53", "synonyms": [ "LFS1", "p53" ], "dgi": { "version": "22_sep_2019", "items": [ { "drug_name_primary": "Vx-970", "drug_chembl_id": "CHEMBL3545202", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": [ { "name": "Ovarian Cancer", "id": 30010000007226 } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": [ { "combination_therapy": "Carboplatin + VX-970" }, { "response_type": "sensitive" }, { "approval_status": "Phase I" }, { "evidence_type": "Actionable" } ] }, { "drug_name_primary": "Mitomycin", "drug_chembl_id": "CHEMBL105", "drug_immunotherapy": true, "drug_antineoplastic": null, "disease": null, "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": true, "attributes": [ { "drug_family": "Chemotherapy" }, { "alteration": "TP53:." } ] }, { "drug_name_primary": "Alvespimycin", "drug_chembl_id": "CHEMBL383824", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": [ { "name": "Advanced Solid Tumor" } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": [ { "combination_therapy": "Alvespimycin + Vorinostat" }, { "response_type": "sensitive" }, { "approval_status": "Preclinical" }, { "evidence_type": "Actionable" } ] }, { "drug_name_primary": "Pramlintide", "drug_chembl_id": "CHEMBL2103758", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": null, "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": true, "attributes": [ { "drug_family": "Amylin analogue" }, { "alteration": "TP53:." }, { "alteration": "TP53:del" } ] }, { "drug_name_primary": "Rg-547", "drug_chembl_id": "CHEMBL384304", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": [ { "name": "Breast Carcinoma", "id": 30010000004289 }, { "name": "Cervical Cancer", "id": 30010000002466 }, { "name": "Colon Carcinoma", "id": 30010000001635 }, { "name": "Lung Carcinoma", "id": 30010000004424 }, { "name": "Mantle Cell Lymphoma", "id": 30010000017748 }, { "name": "Melanoma", "id": 30010000004393 }, { "name": "Osteosarcoma", "id": 30010000002150 }, { "name": "Prostate Carcinoma", "id": 30010000004444 } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": [ { "response_type": "sensitive" }, { "approval_status": "Preclinical - Cell line xenograft" }, { "evidence_type": "Actionable" }, { "approval_status": "Preclinical" } ] }, { "drug_name_primary": "Azd-5363", "drug_chembl_id": "CHEMBL2178577", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": [ { "name": "Prostate Cancer", "id": 30010000007369 } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": [ { "response_type": "sensitive" }, { "approval_status": "Preclinical" }, { "evidence_type": "Actionable" } ] }, { "drug_name_primary": "Rizatriptan", "drug_chembl_id": "CHEMBL905", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": null, "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": true, "attributes": null }, { "drug_name_primary": "Methimazole", "drug_chembl_id": "CHEMBL1515", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": null, "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": true, "attributes": null }, { "drug_name_primary": "Encorafenib", "drug_chembl_id": "CHEMBL3301612", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": [ { "name": "Melanoma", "id": 30010000004393 } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": [ { "combination_therapy": "CGM097 + LGX818" }, { "response_type": "sensitive" }, { "approval_status": "Preclinical" }, { "evidence_type": "Actionable" } ] }, { "drug_name_primary": "Ganetespib", "drug_chembl_id": "CHEMBL2103879", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": [ { "name": "Advanced Solid Tumor" }, { "name": "Breast Cancer", "id": 30010000006325 }, { "name": "Ovarian Cancer", "id": 30010000007226 }, { "name": "Prostate Cancer", "id": 30010000007369 } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": [ { "response_type": "resistant" }, { "approval_status": "Preclinical" }, { "evidence_type": "Actionable" }, { "response_type": "sensitive" } ] }, { "drug_name_primary": "Dabrafenib", "drug_chembl_id": "CHEMBL2028663", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": [ { "name": "Colorectal Cancer", "id": 30010000004812 } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": true, "attributes": [ { "combination_therapy": "ABT-263 + CGM097 + Dabrafenib + PF-04217903" }, { "response_type": "sensitive" }, { "approval_status": "Preclinical - Cell culture" }, { "evidence_type": "Actionable" }, { "combination_therapy": "ABT-263 + Alpelisib + Dabrafenib + Erlotinib" } ] }, { "drug_name_primary": "Streptonigrin", "drug_chembl_id": "CHEMBL11417", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": null, "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": null }, { "drug_name_primary": "Azd-6738", "drug_chembl_id": "CHEMBL3545178", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": [ { "name": "Chronic Lymphocytic Leukemia", "id": 30010000004250 }, { "name": "Colorectal Cancer", "id": 30010000004812 }, { "name": "Lung Carcinoma", "id": 30010000004424 }, { "name": "Pharynx Squamous Cell Carcinoma", "id": 30010000000319 }, { "name": "Tongue Squamous Cell Carcinoma", "id": 30010000000294 } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": [ { "drug_family": "ATR inhibitor" }, { "alteration": "TP53:del" }, { "alteration": "TP53:." }, { "combination_therapy": "AZD6738 + Radiotherapy" }, { "response_type": "sensitive" }, { "approval_status": "Preclinical - Cell culture" }, { "evidence_type": "Actionable" }, { "approval_status": "Preclinical - Cell line xenograft" }, { "combination_therapy": "AZD6738 + Ibrutinib" }, { "approval_status": "Preclinical" } ] }, { "drug_name_primary": "Selumetinib", "drug_chembl_id": "CHEMBL1614701", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": [ { "name": "Colorectal Cancer", "id": 30010000004812 }, { "name": "Melanoma", "id": 30010000004393 } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": [ { "response_type": "decreased response" }, { "approval_status": "Preclinical - Pdx" }, { "evidence_type": "Actionable" }, { "combination_therapy": "Selumetinib + BEZ235" }, { "response_type": "no benefit" }, { "response_type": "sensitive" }, { "approval_status": "Preclinical" }, { "response_type": "resistant" }, { "response_type": "predicted – sensitive" } ] }, { "drug_name_primary": "Temozolomide", "drug_chembl_id": "CHEMBL810", "drug_immunotherapy": true, "drug_antineoplastic": null, "disease": [ { "name": "Ovarian Cancer", "id": 30010000007226 } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": true, "attributes": [ { "combination_therapy": "NU6027 + Temozolomide" }, { "response_type": "predicted – sensitive" }, { "approval_status": "Preclinical - Cell culture" }, { "evidence_type": "Actionable" } ] }, { "drug_name_primary": "Tepotinib", "drug_chembl_id": "CHEMBL3402762", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": [ { "name": "Stomach Carcinoma", "id": 30010000004252 } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": [ { "combination_therapy": "EMD 1214063 + Radiotherapy" }, { "response_type": "sensitive" }, { "approval_status": "Preclinical - Cell culture" }, { "evidence_type": "Actionable" } ] }, { "drug_name_primary": "Trifluoperazine", "drug_chembl_id": "CHEMBL422", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": null, "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": true, "attributes": null }, { "drug_name_primary": "Zinc Chloride", "drug_chembl_id": "CHEMBL1200679", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": null, "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": true, "attributes": null }, { "drug_name_primary": "Cetuximab", "drug_chembl_id": "CHEMBL1201577", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": null, "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": true, "attributes": null }, { "drug_name_primary": "Navitoclax", "drug_chembl_id": "CHEMBL443684", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": [ { "name": "Colorectal Cancer", "id": 30010000004812 }, { "name": "Glioblastoma Multiforme", "id": 30010000017081 } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": [ { "combination_therapy": "Navitoclax + ONC201" }, { "response_type": "sensitive" }, { "approval_status": "Preclinical - Cell culture" }, { "evidence_type": "Actionable" }, { "combination_therapy": "ABT-263 + CGM097 + Dabrafenib + PF-04217903" }, { "combination_therapy": "ABT-263 + Alpelisib + CGM097 + Trametinib" }, { "combination_therapy": "ABT-263 + Alpelisib + Dabrafenib + Erlotinib" }, { "combination_therapy": "ABT-263 + Alpelisib + Erlotinib + Trametinib" } ] }, { "drug_name_primary": "Garlic", "drug_chembl_id": "CHEMBL2108463", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": null, "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": null }, { "drug_name_primary": "Gossypol", "drug_chembl_id": "CHEMBL51483", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": null, "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": null }, { "drug_name_primary": "Chembl1235116", "drug_chembl_id": "CHEMBL1235116", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": null, "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": null }, { "drug_name_primary": "Carboplatin", "drug_chembl_id": "CHEMBL1351", "drug_immunotherapy": true, "drug_antineoplastic": null, "disease": [ { "name": "Neuroblastoma", "id": 30010000004361 }, { "name": "Non-Small Cell Lung Carcinoma", "id": 30010000004509 }, { "name": "Ovarian Cancer", "id": 30010000007226 }, { "name": "Triple-Receptor Negative Breast Cancer", "id": 30010000004736 } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": true, "attributes": [ { "combination_therapy": "MK-1775 + Carboplatin" }, { "response_type": "predicted – resistant" }, { "approval_status": "Phase II" }, { "evidence_type": "Actionable" }, { "combination_therapy": "Carboplatin + VX-970" }, { "response_type": "sensitive" }, { "approval_status": "Phase I" }, { "response_type": "predicted – sensitive" }, { "combination_therapy": "Carboplatin + GSK2830371" }, { "approval_status": "Preclinical" }, { "combination_therapy": "AMG 232 + Carboplatin" }, { "approval_status": "Preclinical - Cell line xenograft" }, { "combination_therapy": "MK-1775 + Carboplatin + Paclitaxel" }, { "combination_therapy": "Carboplatin + Nutlin-3" }, { "approval_status": "Preclinical - Cell culture" } ] }, { "drug_name_primary": "Vesnarinone", "drug_chembl_id": "CHEMBL17423", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": null, "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": null }, { "drug_name_primary": "Puromycin", "drug_chembl_id": "CHEMBL469912", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": null, "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": null }, { "drug_name_primary": "Chembl392068", "drug_chembl_id": "CHEMBL392068", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": [ { "name": "Lung Cancer", "id": 30010000007947 } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": [ { "combination_therapy": "7RH + LY411575" }, { "response_type": "sensitive" }, { "approval_status": "Preclinical" }, { "evidence_type": "Actionable" } ] }, { "drug_name_primary": "Etoposide", "drug_chembl_id": "CHEMBL44657", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": [ { "name": "Ovarian Cancer", "id": 30010000007226 } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": true, "attributes": [ { "combination_therapy": "Nutlin-3 + Etoposide" }, { "response_type": "sensitive" }, { "approval_status": "Preclinical" }, { "evidence_type": "Actionable" } ] }, { "drug_name_primary": "Cyclophosphamide", "drug_chembl_id": "CHEMBL88", "drug_immunotherapy": true, "drug_antineoplastic": null, "disease": [ { "name": "Breast Cancer", "id": 30010000006325 }, { "name": "Estrogen-Receptor Negative Breast Cancer", "id": 30010000005628 }, { "name": "Neuroblastoma", "id": 30010000004361 } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": true, "attributes": [ { "combination_therapy": "Crizotinib + Cyclophosphamide + Topotecan" }, { "response_type": "no benefit" }, { "approval_status": "Preclinical" }, { "evidence_type": "Actionable" }, { "combination_therapy": "Epirubicin + Cyclophosphamide" }, { "approval_status": "Phase I" }, { "response_type": "predicted – sensitive" }, { "approval_status": "Preclinical - Cell line xenograft" }, { "response_type": "sensitive" }, { "approval_status": "Preclinical - Pdx" }, { "combination_therapy": "Doxorubicin + Flourouracil + Cyclophosphamide" }, { "combination_therapy": "Cyclophosphamide + Topotecan" }, { "response_type": "not applicable" } ] }, { "drug_name_primary": "Pha-680632", "drug_chembl_id": "CHEMBL363160", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": [ { "name": "Colorectal Cancer", "id": 30010000004812 } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": [ { "combination_therapy": "PHA-680632 + Radiotherapy" }, { "response_type": "sensitive" }, { "approval_status": "Preclinical - Pdx" }, { "evidence_type": "Actionable" } ] }, { "drug_name_primary": "Ly-3009120", "drug_chembl_id": "CHEMBL3545195", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": [ { "name": "Melanoma", "id": 30010000004393 } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": [ { "response_type": "sensitive" }, { "approval_status": "Preclinical" }, { "evidence_type": "Actionable" } ] }, { "drug_name_primary": "Azd-1775", "drug_chembl_id": "CHEMBL1976040", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": [ { "name": "Advanced Solid Tumor" }, { "name": "Breast Cancer", "id": 30010000006325 }, { "name": "Colon Cancer", "id": 30010000001635 }, { "name": "Glioblastoma Multiforme", "id": 30010000017081 }, { "name": "Non-Small Cell Lung Carcinoma", "id": 30010000004509 }, { "name": "Ovarian Cancer", "id": 30010000007226 }, { "name": "Pancreatic Cancer", "id": 30010000004475 }, { "name": "Sarcoma", "id": 30010000004377 } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": [ { "drug_family": "WEE1 inhibitor" }, { "alteration": "TP53:." }, { "combination_therapy": "MK-1775 + Carboplatin" }, { "response_type": "predicted – resistant" }, { "approval_status": "Phase II" }, { "evidence_type": "Actionable" }, { "response_type": "predicted – sensitive" }, { "combination_therapy": "MK-1775 + PF-00477736" }, { "response_type": "sensitive" }, { "approval_status": "Preclinical" }, { "combination_therapy": "MK-1775 + Gemcitabine" }, { "approval_status": "Preclinical - Pdx u0026 cell culture" }, { "combination_therapy": "MK-1775 + Cisplatin" }, { "approval_status": "Preclinical - Cell culture" }, { "approval_status": "Preclinical - Pdx" }, { "combination_therapy": "MK-1775 + Radiotherapy" }, { "combination_therapy": "MK-1775 + Carboplatin + Paclitaxel" }, { "approval_status": "Phase I" }, { "approval_status": "Preclinical - Cell line xenograft" } ] }, { "drug_name_primary": "Pf-00477736", "drug_chembl_id": "CHEMBL3545137", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": [ { "name": "Colon Cancer", "id": 30010000001635 } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": [ { "combination_therapy": "MK-1775 + PF-00477736" }, { "response_type": "sensitive" }, { "approval_status": "Preclinical" }, { "evidence_type": "Actionable" } ] }, { "drug_name_primary": "Mycophenolic Acid", "drug_chembl_id": "CHEMBL866", "drug_immunotherapy": true, "drug_antineoplastic": null, "disease": null, "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": true, "attributes": null }, { "drug_name_primary": "Bevacizumab", "drug_chembl_id": "CHEMBL1201583", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": [ { "name": "Advanced Solid Tumor" }, { "name": "Breast Cancer", "id": 30010000006325 }, { "name": "Colorectal Cancer", "id": 30010000004812 } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": true, "attributes": [ { "combination_therapy": "Avastin + Doxorubicin + Docetaxel" }, { "response_type": "sensitive" }, { "approval_status": "Phase I" }, { "evidence_type": "Actionable" }, { "approval_status": "Phase III" }, { "approval_status": "Clinical Study" } ] }, { "drug_name_primary": "Aspirin", "drug_chembl_id": "CHEMBL25", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": null, "gene_symbol": "TP53", "interaction_type": [ "acetylation" ], "drug_fda_approved": true, "attributes": null }, { "drug_name_primary": "Epirubicin", "drug_chembl_id": "CHEMBL417", "drug_immunotherapy": true, "drug_antineoplastic": null, "disease": [ { "name": "Breast Cancer", "id": 30010000006325 } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": true, "attributes": [ { "combination_therapy": "Epirubicin + Cyclophosphamide" }, { "response_type": "no benefit" }, { "approval_status": "Phase I" }, { "evidence_type": "Actionable" }, { "response_type": "sensitive" } ] }, { "drug_name_primary": "Ink-128", "drug_chembl_id": "CHEMBL3545056", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": [ { "name": "Colorectal Cancer", "id": 30010000004812 }, { "name": "Skin Cancer", "id": 30010000002393 } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": [ { "combination_therapy": "MLN0128 + PD-0325901" }, { "response_type": "no benefit" }, { "approval_status": "Preclinical - 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Cell line xenograft" }, { "approval_status": "Preclinical - Cell culture" } ] }, { "drug_name_primary": "Rituximab", "drug_chembl_id": "CHEMBL1201576", "drug_immunotherapy": true, "drug_antineoplastic": null, "disease": null, "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": true, "attributes": null }, { "drug_name_primary": "Ds-7423", "drug_chembl_id": "CHEMBL3545248", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": [ { "name": "Ovarian Clear Cell Adenocarcinoma", "id": 30010000005238 } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": [ { "response_type": "decreased response" }, { "approval_status": "Preclinical - Cell culture" }, { "evidence_type": "Actionable" }, { "approval_status": "Preclinical" } ] }, { "drug_name_primary": "Tirapazamine", "drug_chembl_id": "CHEMBL50882", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": null, "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": null }, { "drug_name_primary": "Pimasertib", "drug_chembl_id": "CHEMBL2107832", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": [ { "name": "Pancreatic Cancer", "id": 30010000004475 } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": [ { "combination_therapy": "Pimasertib + Gemcitabine" }, { "response_type": "sensitive" }, { "approval_status": "Preclinical" }, { "evidence_type": "Actionable" } ] }, { "drug_name_primary": "Inositol", "drug_chembl_id": "CHEMBL1222251", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": null, "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": null }, { "drug_name_primary": "Pd-0325901", "drug_chembl_id": "CHEMBL507361", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": [ { "name": "Colorectal Cancer", "id": 30010000004812 } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": false, "attributes": [ { "combination_therapy": "MLN0128 + PD-0325901" }, { "response_type": "no benefit" }, { "approval_status": "Preclinical - Pdx" }, { "evidence_type": "Actionable" }, { "response_type": "sensitive" }, { "approval_status": "Preclinical - Cell culture" }, { "approval_status": "Preclinical - Cell line xenograft" }, { "response_type": "predicted – sensitive" }, { "approval_status": "Preclinical - Pdx u0026 cell culture" } ] }, { "drug_name_primary": "Interferon Alfa-2B", "drug_chembl_id": "CHEMBL1201558", "drug_immunotherapy": true, "drug_antineoplastic": null, "disease": null, "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": true, "attributes": null }, { "drug_name_primary": "Crizotinib", "drug_chembl_id": "CHEMBL601719", "drug_immunotherapy": false, "drug_antineoplastic": null, "disease": [ { "name": "Breast Cancer", "id": 30010000006325 }, { "name": "Histiocytic And Dendritic Cell Cancer", "id": 30010000005410 }, { "name": "Neuroblastoma", "id": 30010000004361 } ], "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": true, "attributes": [ { "combination_therapy": "Crizotinib + Cyclophosphamide + Topotecan" }, { "response_type": "no benefit" }, { "approval_status": "Preclinical" }, { "evidence_type": "Actionable" }, { "response_type": "predicted – sensitive" }, { "approval_status": "Preclinical - Cell line xenograft" }, { "response_type": "sensitive" }, { "approval_status": "Preclinical - Pdx" }, { "approval_status": "Clinical Study" } ] }, { "drug_name_primary": "Thiotepa", "drug_chembl_id": "CHEMBL671", "drug_immunotherapy": true, "drug_antineoplastic": null, "disease": null, "gene_symbol": "TP53", "interaction_type": null, "drug_fda_approved": true, "attributes": null } ] }, "cgd": { "version": "05_nov_2019", "pub_med_references": [ 1349175, 1565143, 1565144, 1591732, 1679237, 1978757, 3409256, 6016796, 7887414, 8118819, 8718514, 9242456, 10612830, 11219776, 11332399, 11481490, 11498785, 11600572, 12085209, 12524418, 12610779, 12619118, 14583457, 15381368, 15695383, 15741269, 15977174, 18762572, 19171829, 19556618, 19652052, 20301488, 21056402, 21601526, 21837677, 21946351, 21990040, 22170717, 22551548, 22672556, 22878818, 22939227, 23015295, 23175693, 23355100, 23409989, 23667851, 23894400, 30146126 ], "condition": "Li-Fraumeni syndrome; Choroid plexus papilloma; Ependymoma, intracranial; Osteogenic sarcoma; Breast cancer, familial; Hepatoblastoma; Non-Hodgkin lymphoma; Adrenocortical carcinoma; Colorectal cancer; Bone marrow failure syndrome 5", "inheritance": "AD", "age_group": "Pediatric", "intervention_categories": [ "Oncologic" ], "comments": "Variants may also be involved in susceptibility to a number of types of neoplasms (eg, Basal cell carcinoma, susceptibility to, Glioma, susceptibility to)", "intervention": null }, "civic": { "version": "08_jan_2020", "items": [ { "variant": "DELETERIOUS MUTATION", "variant_summary": "Deleterious mutations are mutations of TP53 with prior characterization demonstrating significant deleterious effect on TP53 protein function. Inactivating TP53 mutations prevent on target activity and efficacy of MDM2-TP53 interaction inhibitors.", "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/221", "variant_origin": "Somatic", "pub_med_references": [ 22090360 ], "clinical_significance": "Poor Outcome", "evidence_level": "B", "evidence_statement": "In a study of 74 patients with head and neck squamous cell carcinoma, those with disruptive mutations in TP53 had shorter overall survival and a higher rate of locoregional recurrence than those without mutations or with nondisruptive mutations.", "evidence_type": "Prognostic", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/517", "drugs": null, "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Head And Neck Squamous Cell Carcinoma", "rating": "3", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "5520" }, { "variant": "MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/222", "variant_origin": "Somatic", "pub_med_references": [ 8901856 ], "clinical_significance": "Poor Outcome", "evidence_level": "B", "evidence_statement": "Unlike other studies, in this study of 110 patients with head and neck squamous cell carcinoma, there was no significant difference in the overall survival of patients with and without any TP53 mutations.", "evidence_type": "Prognostic", "evidence_status": "accepted", "evidence_direction": "Does Not Support", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/518", "drugs": null, "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Head And Neck Squamous Cell Carcinoma", "rating": "3", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "5520" }, { "variant": "MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/222", "variant_origin": "Somatic", "pub_med_references": [ 19941080 ], "clinical_significance": "Poor Outcome", "evidence_level": "B", "evidence_statement": "In a retrospective study of patients with esophageal carcinoma, those with mutations in TP53 had worse overall survival.", "evidence_type": "Prognostic", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/519", "drugs": null, "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Esophagus Squamous Cell Carcinoma", "rating": "4", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "3748" }, { "variant": "MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/222", "variant_origin": "Somatic", "pub_med_references": [ 22699455 ], "clinical_significance": "Poor Outcome", "evidence_level": "B", "evidence_statement": "In children with bone marrow relapsed B-cell precursor acute lymphoblastic leukemia, in multivariate analysis those with mutations in TP53 had worse event-free survival than patients without mutations.", "evidence_type": "Prognostic", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/520", "drugs": null, "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Precursor B Lymphoblastic Lymphoma/leukemia", "rating": "4", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "7061" }, { "variant": "MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/222", "variant_origin": "Somatic", "pub_med_references": [ 24836762 ], "clinical_significance": "Poor Outcome", "evidence_level": "B", "evidence_statement": "In patients with myelodysplastic syndrome, in a multivariate analysis those with mutations in TP53 had shorter overall survival than wild-type patients.", "evidence_type": "Prognostic", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/521", "drugs": null, "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Myelodysplastic Syndrome", "rating": "4", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "0050908" }, { "variant": "MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/222", "variant_origin": "Somatic", "pub_med_references": [ 17215851 ], "clinical_significance": "Poor Outcome", "evidence_level": "B", "evidence_statement": "In patients with myeloma, those with mutations in TP53 had worse overall survival than those without.", "evidence_type": "Prognostic", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/522", "drugs": null, "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Myeloma", "rating": "4", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "0070004" }, { "variant": "MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/222", "variant_origin": "Somatic", "pub_med_references": [ 11325447 ], "clinical_significance": "Poor Outcome", "evidence_level": "B", "evidence_statement": "Tumors from 114 patients with head and neck squamous cell carcinoma were analyzed for TP53 mutations, 21 of which were treated with surgery. Unlike those treated with radiotherapy, those treated with surgery did not show a significant difference in rates of loco-regional control between those with and without mutations in TP53.", "evidence_type": "Prognostic", "evidence_status": "accepted", "evidence_direction": "Does Not Support", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/523", "drugs": null, "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Head And Neck Squamous Cell Carcinoma", "rating": "4", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "5520" }, { "variant": "MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/222", "variant_origin": "Somatic", "pub_med_references": [ 11325447 ], "clinical_significance": "Poor Outcome", "evidence_level": "B", "evidence_statement": "Tumors from 114 patients with head and neck squamous cell carcinoma were analyzed for TP53 mutations. Of the 93 patients treated with radiotherapy, patients with mutations in TP53 had lower rates of loco-regional control and shorter disease-free, disease-specific, and overall survival.", "evidence_type": "Prognostic", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/524", "drugs": null, "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Head And Neck Squamous Cell Carcinoma", "rating": "4", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "5520" }, { "variant": "TRUNCATING MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/223", "variant_origin": "Somatic", "pub_med_references": [ 21467160 ], "clinical_significance": "Poor Outcome", "evidence_level": "B", "evidence_statement": "In patients with head and neck squamous cell carcinoma, in a multivariate analysis those with truncating mutations in TP53 had worse progression-free and overall survival than wild-type patients.", "evidence_type": "Prognostic", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/525", "drugs": null, "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Head And Neck Squamous Cell Carcinoma", "rating": "4", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "5520" }, { "variant": "TRUNCATING MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/223", "variant_origin": "Somatic", "pub_med_references": [ 21467160 ], "clinical_significance": "Poor Outcome", "evidence_level": "B", "evidence_statement": "In patients with head and neck squamous cell carcinoma, when comparing patients with any mutation in TP53 to wild-type, there was not a significant difference in overall survival in a multivariate analysis.", "evidence_type": "Prognostic", "evidence_status": "accepted", "evidence_direction": "Does Not Support", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/526", "drugs": null, "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Head And Neck Squamous Cell Carcinoma", "rating": "4", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "5520" }, { "variant": "MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/222", "variant_origin": "Somatic", "pub_med_references": [ 21747090 ], "clinical_significance": "Poor Outcome", "evidence_level": "B", "evidence_statement": "In relapsed B-ALL patients, TP53 mutations were associated with morphologic nonresponse to therapy (>5% blasts in the bone marrow after 9 weeks of treatment) as well as reduced event free and overall survival when compared to TP53 wildtype patients.", "evidence_type": "Prognostic", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/640", "drugs": null, "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Precursor B Lymphoblastic Lymphoma/leukemia", "rating": "4", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "7061" }, { "variant": "DNA BINDING DOMAIN MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/242", "variant_origin": "Somatic", "pub_med_references": [ 12509970 ], "clinical_significance": "Poor Outcome", "evidence_level": "B", "evidence_statement": "Oral squamous cell carcinoma patients with TP53 mutations in the DNA binding domain (L2, L3 and the LSH motif) have significantly reduced cumulative survival when compared to patients with TP53 mutations outside of this DNA binding domain. These mutations were also significantly associated with locoregional failure, cervical lymph node metastasis and distant metastasis, likely contributing to this finding.", "evidence_type": "Prognostic", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/641", "drugs": null, "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Oral Squamous Cell Carcinoma", "rating": "4", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "0050866" }, { "variant": "MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/222", "variant_origin": "Somatic", "pub_med_references": [ 24740294 ], "clinical_significance": "Sensitivity/Response", "evidence_level": "B", "evidence_statement": "In this meta-analysis of 13 studies (564 patients) p53 positivity as defined by high protein expression and/or p53 mutation was associated with improved response to chemotherapy (risk ratio [RR] = 0.704; 95% confidence intervals [CI] = 0.550-0.903; P = 0.006).", "evidence_type": "Predictive", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/850", "drugs": [ "Chemotherapy" ], "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Gastric Adenocarcinoma", "rating": "3", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "3717" }, { "variant": "MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/222", "variant_origin": "Somatic", "pub_med_references": [ 22698404 ], "clinical_significance": "Sensitivity/Response", "evidence_level": "D", "evidence_statement": "In this preclinical study, MMTV-Wnt1 mammary tumors with mutant TP53 showed a better clinical response to chemotherapy (doxorubicin) than TP53 wild-type tumors. This was mediated by wild-type TP53-induced cell-arrest under chemotherapy even in the context of heterozygous TP53 point mutations or absence of p21. Thus the status of both TP53 alleles should be assessed because even one copy of wild-type TP53 may contribute to poor response to chemotherapy.", "evidence_type": "Predictive", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/851", "drugs": [ "Doxorubicin" ], "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Breast Cancer", "rating": "4", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "1612" }, { "variant": "WILD TYPE", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/369", "variant_origin": null, "pub_med_references": [ 24957073 ], "clinical_significance": "Sensitivity/Response", "evidence_level": "B", "evidence_statement": "In this retrospective biomarker analysis of the EXPERT-C trial, patients with TP53 wild-type status had a statistically significant better progression free survival (PFS) (89.3% vs 65.0% at 5 years; hazard ratio [HR] = 0.23; 95% confidence interval [CI] = 0.07 to 0.78; two-sided P = .02 by Cox regression) and overall survival (OS) (92.7% vs 67.5% at 5 years; HR = 0.16; 95% CI = 0.04 to 0.70; two-sided P = .02 by Cox regression) when treated with Cetuximab + CAPOX (Capecitabine, Oxaliplatin) than in the control arm without Cetuximab.", "evidence_type": "Predictive", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/875", "drugs": [ "Oxaliplatin", "Cetuximab", "Capecitabine" ], "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Colorectal Cancer", "rating": "3", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "9256" }, { "variant": "WILD TYPE", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/369", "variant_origin": null, "pub_med_references": [ 23515910 ], "clinical_significance": "Sensitivity/Response", "evidence_level": "B", "evidence_statement": "Patients with p53 wild type (as defined by low expression and/or wild-type tp53 gene) had a higher response rate to chemotherapy-based treatment (total major response [MR]: risk ratio [RR] = 1.09, 95 % CI = 1.03-1.16, P = .003; pathological MR: RR = 1.15, 95 % CI = 1.06-1.25, P = .001; total complete response [CR]: RR = 1.08, 95 % CI = 1.00-1.17, P = .040) in this meta-analysis (28 studies, 1497 cases).", "evidence_type": "Predictive", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/906", "drugs": [ "Chemotherapy" ], "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Esophageal Carcinoma", "rating": "3", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "1107" }, { "variant": "MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/222", "variant_origin": "Somatic", "pub_med_references": [ 26771088 ], "clinical_significance": "Poor Outcome", "evidence_level": "B", "evidence_statement": "In a study of 97 patients with AML treated with HSCT, 40 had TP53 mutations comprising a total of 44 mutations. Patients with a TP53 mutation had a reduced three year probability of overall survival and event-free survival compared to patients with the wild-type TP53.", "evidence_type": "Prognostic", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/1018", "drugs": null, "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Acute Myeloid Leukemia", "rating": "4", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "9119" }, { "variant": "MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/222", "variant_origin": "Somatic", "pub_med_references": [ 15922892 ], "clinical_significance": "Poor Outcome", "evidence_level": "B", "evidence_statement": "TP53 mutation was shown to be associated with shorter overall survival in patients with adrenocortical tumors (log-rank test; P=0.098). Of 20 patients studied, 5 had coding mutation in TP53. Four of the 5 patients with a TP53 mutation had metastases at diagnosis or detected soon thereafter, and 3 of 4 died of disease within 12 months of surgical resection.", "evidence_type": "Prognostic", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/1028", "drugs": null, "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Adrenocortical Carcinoma", "rating": "2", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "3948" }, { "variant": "MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/222", "variant_origin": "Somatic", "pub_med_references": [ 22425996 ], "clinical_significance": "Sensitivity/Response", "evidence_level": "D", "evidence_statement": "A clinical trial comparing selumetinib and docetaxel vs. docetaxel and placebo in KRAS mutant NSCLC was recapitulated in mice. Tumors were induced in lung epithelium by nasal instillation of CRE-bearing adenovirus in conditionally targeted mice. Kras(G12D) and Trp53 knockout mutant mice were resistant to docetaxel monotherapy but sensitive to combined treatment. In a small number of human NSCLC patients with these genotypes FDG-PET signal intensity changes and pERK IHC staining correlated with mouse data.", "evidence_type": "Predictive", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/1145", "drugs": [ "Docetaxel", "Selumetinib" ], "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Lung Non-small Cell Carcinoma", "rating": "3", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "3908" }, { "variant": "MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/222", "variant_origin": "Somatic", "pub_med_references": [ 22425996 ], "clinical_significance": "Resistance", "evidence_level": "D", "evidence_statement": "A clinical trial comparing selumetinib and docetaxel vs. docetaxel and placebo in KRAS mutant NSCLC was recapitulated in mice. Tumors were induced in lung epithelium by nasal instillation of CRE-bearing adenovirus in conditionally targeted mice. Kras(G12D) and Trp53 knockout mutant mice were resistant to docetaxel monotherapy but sensitive to combined treatment. In a small number of human NSCLC patients with these genotypes FDG-PET signal intensity changes and pERK IHC staining correlated with mouse data.", "evidence_type": "Predictive", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/1146", "drugs": [ "Docetaxel" ], "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Lung Non-small Cell Carcinoma", "rating": "3", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "3908" }, { "variant": "DELETERIOUS MUTATION", "variant_summary": "Deleterious mutations are mutations of TP53 with prior characterization demonstrating significant deleterious effect on TP53 protein function. Inactivating TP53 mutations prevent on target activity and efficacy of MDM2-TP53 interaction inhibitors.", "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/221", "variant_origin": "Somatic", "pub_med_references": [ 26899019 ], "clinical_significance": "Poor Outcome", "evidence_level": "B", "evidence_statement": "Pooled analysis of TP53 mutations (exons 5-8) from 4 randomized trials (IALT, JBR10, CALGB-9633 and ANITA). Mutations (434; 36%) had no prognostic effect (OBS: HROS=0.99; [95%CI 0.77-1.28], p=0.95; HRDFS=0.99 [0.78-1.25], p=0.92) but were marginally predictive of benefit from ACT for OS (test for interaction: OS: p=0.06; DFS: p=0.11).", "evidence_type": "Prognostic", "evidence_status": "accepted", "evidence_direction": "Does Not Support", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/1147", "drugs": null, "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Lung Non-small Cell Carcinoma", "rating": "4", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "3908" }, { "variant": "DELETERIOUS MUTATION", "variant_summary": "Deleterious mutations are mutations of TP53 with prior characterization demonstrating significant deleterious effect on TP53 protein function. Inactivating TP53 mutations prevent on target activity and efficacy of MDM2-TP53 interaction inhibitors.", "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/221", "variant_origin": "Somatic", "pub_med_references": [ 26899019 ], "clinical_significance": "Sensitivity/Response", "evidence_level": "B", "evidence_statement": "Pooled analysis of TP53 mutations (exons 5-8) from 4 randomized trials (IALT, JBR10, CALGB-9633 and ANITA) of platinum-based adjuvant chemotherapy (ACT) versus observation (OBS). Patients with TP53wt had significantly better PFS and OS with ACT vs. OBS (p=0.005, p=0.02, respectively) whereas patients with TP53 mutations did not show significant differences in PFS and OS between ACT and OBS (p=0.86, p=0.63).", "evidence_type": "Predictive", "evidence_status": "accepted", "evidence_direction": "Does Not Support", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/1148", "drugs": [ "Adjuvant Chemotherapy" ], "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Lung Non-small Cell Carcinoma", "rating": "2", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "3908" }, { "variant": "WILD TYPE", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/369", "variant_origin": null, "pub_med_references": [ 26899019 ], "clinical_significance": "Sensitivity/Response", "evidence_level": "B", "evidence_statement": "Pooled analysis of TP53 mutations (exons 5-8) from 4 randomized trials (IALT, JBR10, CALGB-9633 and ANITA, 1209 patients, median follow-up 5.5 years) of platinum-based adjuvant chemotherapy (ACT) versus observation (OBS). Patients with wild-type TP53 had better outcomes with ACT than OBS (HROS=0.77 [0.62-0.95], p=0.02; HRDFS=0.75 [0.62-0.92], p=0.005).", "evidence_type": "Predictive", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/1149", "drugs": [ "Adjuvant Chemotherapy" ], "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Lung Non-small Cell Carcinoma", "rating": "3", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "3908" }, { "variant": "DELETERIOUS MUTATION", "variant_summary": "Deleterious mutations are mutations of TP53 with prior characterization demonstrating significant deleterious effect on TP53 protein function. Inactivating TP53 mutations prevent on target activity and efficacy of MDM2-TP53 interaction inhibitors.", "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/221", "variant_origin": "Somatic", "pub_med_references": [ 26646755 ], "clinical_significance": "Sensitivity/Response", "evidence_level": "B", "evidence_statement": "19 advanced sarcoma patients treated with pazopanib were retrospectively assessed for mutations associated with response using the Foundation one sarcoma/heme panel. Progression-free survival (PFS) of patients with TP53 mutations (all predicted to be loss of function) was significantly greater than TP53 wild-type tumors with the median PFS of 208 versus 136 days, respectively [P = 0.036, hazards ratio 0.38 (95% confidence interval 0.09-0.83)].", "evidence_type": "Predictive", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/1170", "drugs": [ "Pazopanib" ], "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Sarcoma", "rating": "2", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "1115" }, { "variant": "MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/222", "variant_origin": "Somatic", "pub_med_references": [ 8241511 ], "clinical_significance": "Poor Outcome", "evidence_level": "B", "evidence_statement": "A study of 53 patients with B-CLL found a significant resistance to chemotherapy and corresponding poor clinical outcomes among the 7 treated patients with p53 mutations compared to the 29 treated patients without.", "evidence_type": "Prognostic", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/1450", "drugs": null, "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Chronic Lymphocytic Leukemia", "rating": "3", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "1040" }, { "variant": "MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/222", "variant_origin": "Somatic", "pub_med_references": [ 18689542 ], "clinical_significance": "Poor Outcome", "evidence_level": "B", "evidence_statement": "In a study of 126 patients with long-term follow-up, TP53 mutations were significantly associated with shorter median survival in patients (P = 0.002) from time of diagnosis. The median survival from the time of first observation of a TP53 mutation was much more pronounced (P = <0.001). These findings were statistically independent of 17p deletions.", "evidence_type": "Prognostic", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/1451", "drugs": null, "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Chronic Lymphocytic Leukemia", "rating": "4", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "1040" }, { "variant": "MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/222", "variant_origin": "Somatic", "pub_med_references": [ 20697090 ], "clinical_significance": "Poor Outcome", "evidence_level": "B", "evidence_statement": "The authors analyzed 328 patients with CLL, of which 28 were identified to have TP53 mutations. Patients with TP53 mutations were found to have significantly shorter progression-free (HR = 3.8; P < 0.001) and overall survival (HR = 7.2; P < 0.001).", "evidence_type": "Prognostic", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/1452", "drugs": null, "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Chronic Lymphocytic Leukemia", "rating": "5", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "1040" }, { "variant": "MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/222", "variant_origin": "Somatic", "pub_med_references": [ 21483000 ], "clinical_significance": "Poor Outcome", "evidence_level": "B", "evidence_statement": "In the CLL4 trial assessing first line treatment with chlorambucil or fludarabine with or without cyclophosphamide, patients with TP53 mutations experienced poorer overall response rates (27% vs 83%), shorter progression free survival (5 year PFS 5% vs 17%), and overall survival (20% vs 59%) compared to patients without TP53 mutations.", "evidence_type": "Prognostic", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/1478", "drugs": null, "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Chronic Lymphocytic Leukemia", "rating": "3", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "1040" }, { "variant": "MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/222", "variant_origin": "Somatic", "pub_med_references": [ 14726385 ], "clinical_significance": "Sensitivity/Response", "evidence_level": "B", "evidence_statement": "Thirty-six patients with CLL were treated with alemtuzumab. Partial or complete response was achieved in 6 of 15 patients with p53 mutations, compared to 4 of 21 without. These findings are not statistically significant, but the authors suggest that alemtuzumab is an effective therapy for patients with p53 mutations or deletions.", "evidence_type": "Predictive", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/1481", "drugs": [ "Alemtuzumab" ], "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Chronic Lymphocytic Leukemia", "rating": "2", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "1040" }, { "variant": "MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/222", "variant_origin": "Somatic", "pub_med_references": [ 24943832 ], "clinical_significance": "Poor Outcome", "evidence_level": "B", "evidence_statement": "In a multivariate analysis of 774 CLL patients, TP53 aberrations were significantly correlated with shorter time to first treatment (HR=2.081; 95% CI=1.431-3.021). This finding was independent of IGHV mutation status.", "evidence_type": "Prognostic", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/1485", "drugs": null, "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Chronic Lymphocytic Leukemia", "rating": "5", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "1040" }, { "variant": "MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/222", "variant_origin": "Somatic", "pub_med_references": [ 26837699 ], "clinical_significance": "Poor Outcome", "evidence_level": "A", "evidence_statement": "In a cohort of 406 patients with CLL, those patients with clonal or sub-clonal mutations in TP53 had significantly shorter overall survival (HR: 1.71; 95% CI: 1.28-2.26; P = .0001).", "evidence_type": "Prognostic", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/1507", "drugs": null, "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Chronic Lymphocytic Leukemia", "rating": "5", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "1040" }, { "variant": "OVEREXPRESSION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/1306", "variant_origin": "Somatic", "pub_med_references": [ 11595686 ], "clinical_significance": "Poor Outcome", "evidence_level": "B", "evidence_statement": "p53 overexpression (>10% positive stained nuclei) was found in 110 cases from a 178 patient cohort with invasive ovarian carcinoma who had undergone surgery. Overexpression of p53 was correlated with poor differentiation (p<0.001) and high S-phase fraction (p<0.001).", "evidence_type": "Prognostic", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/2697", "drugs": null, "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Ovarian Cancer", "rating": "3", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "2394" }, { "variant": "DNA BINDING DOMAIN MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/242", "variant_origin": "Somatic", "pub_med_references": [ 10786679 ], "clinical_significance": "Resistance", "evidence_level": "B", "evidence_statement": "In a study 202 breast cancer patients undergoing first line tamoxifen treatment, 65 patients had mutations in TP53. Among the p53 wild type population a 66% response rate was reported, where response was considered as complete response, partial response or stable disease. In a patient subgroup with mutations in p53 amino acids that directly interact with DNA, 2 of 11 (18%) of patients responded to tamoxifen.", "evidence_type": "Predictive", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/2783", "drugs": [ "Tamoxifen" ], "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Breast Cancer", "rating": "3", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "1612" }, { "variant": "MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/222", "variant_origin": "Somatic", "pub_med_references": [ 10786679 ], "clinical_significance": "Resistance", "evidence_level": "C", "evidence_statement": "In a study 202 breast cancer patients undergoing tamoxifen treatment, a higher frequency of wildtype TP53 patients responded to treatment compared to those with mutations in TP53 (66% wild-type vs. 31%, odds ratio (OR):0.22, 95CI:0.12-0.42, P<0.0001, univariate analysis; OR:0.29, 95% CI:0.12-0.42, P=0.0014, multivariate analysis). The median survival after start of therapy was shorter in patients with mutations in TP53 than for patients with wild-type TP53 (20mo vs. 29mo, HR:1.99,95% CI:1.43-2.75, P<0.001). Breast cancer patients with TP53 mutations also had a decrease in progression-free survival (HR:2.61, 95% CI:1.90-3.6, P<0.001).", "evidence_type": "Predictive", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/2784", "drugs": [ "Tamoxifen" ], "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Breast Cancer", "rating": "1", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "1612" }, { "variant": "OVEREXPRESSION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/1306", "variant_origin": "Somatic", "pub_med_references": [ 14514923 ], "clinical_significance": "Sensitivity/Response", "evidence_level": "B", "evidence_statement": "In a Phase II trial of 25 patients with metastaic gastric cancer, patients received preoperative high dose chemotherapy (HDCT) consisting of etoposide, cisplatin and mitomycin. Patients with greater than 50% regression in response to HDCT received surgery. TP53 overexpression was assayed by immunohistochemistry. 14 patients showed p53 overexpression, and 12 of these qualified for resection. Overall survival in patients with p53 overexpression was 17.3 months in contrast to patients with negative p53 immunohistochemistry, where it was 7.2 months (p=0.0003).", "evidence_type": "Predictive", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/2799", "drugs": [ "Mitomycin", "Cisplatin", "Etoposide" ], "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Stomach Cancer", "rating": "4", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "10534" }, { "variant": "MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/222", "variant_origin": "Somatic", "pub_med_references": [ 14514923 ], "clinical_significance": "Sensitivity/Response", "evidence_level": "C", "evidence_statement": "In a study of 25 patients with advanced gastric cancer, mutations in TP53 were identified in 32% of primary tumors. TP53 mutations were associated with an improved response to preoperative treatment of a modified EAP protocol (combination of doxorubicin, etoposide and cisplatin). Patients with mutations in TP53 had an increased median survival compared to patients with wildtype TP53 (18.5mo vs. 10.2mo, P=0.044).", "evidence_type": "Predictive", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/2820", "drugs": [ "Doxorubicin", "Cisplatin", "Etoposide" ], "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Stomach Carcinoma", "rating": "1", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "5517" }, { "variant": "WILD TYPE", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/369", "variant_origin": null, "pub_med_references": [ 17671205 ], "clinical_significance": "Sensitivity/Response", "evidence_level": "D", "evidence_statement": "MDM2 Inhibitor Nutlin-3a induced senescence in presence of functional TP53 in murine primary fibroblasts, oncogenically transformed fibroblasts, and fibrosarcoma cell lines. Cells lacking functional TP53 were completely insensitive to the drug.", "evidence_type": "Predictive", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/2963", "drugs": [ "Nutlin-3a" ], "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Cancer", "rating": "4", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "162" }, { "variant": "WILD TYPE", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/369", "variant_origin": null, "pub_med_references": [ 25730903 ], "clinical_significance": "Sensitivity/Response", "evidence_level": "D", "evidence_statement": "MDM2 Inhibitor screen in a panel of 260 cancer cell lines with well characterized TP53 status shows that only cancer cell lines with unaltered TP53 may be sensitive to MDM2 Inhibitor.", "evidence_type": "Predictive", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/2964", "drugs": [ "AMGMDS3" ], "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Cancer", "rating": "4", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "162" }, { "variant": "WILD TYPE", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/369", "variant_origin": null, "pub_med_references": [ 26459177 ], "clinical_significance": "Sensitivity/Response", "evidence_level": "B", "evidence_statement": "Phase I Trial of RG7112 in 116 heavily pretreated patients with AML, ALL, CML, CLL, sCLL demonstrated sustained clinical improvement and induction of TP53 target genes in subset of patients with wild type TP53. 96 patients were tested for TP53 mutation and 19 cases of mutation were detected. No sustained clinical improvement or induction of TP53 target genes was observed in patients with mutant TP53.", "evidence_type": "Predictive", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/2965", "drugs": [ "RG7112" ], "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Leukemia", "rating": "3", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "1240" }, { "variant": "DELETERIOUS MUTATION", "variant_summary": "Deleterious mutations are mutations of TP53 with prior characterization demonstrating significant deleterious effect on TP53 protein function. Inactivating TP53 mutations prevent on target activity and efficacy of MDM2-TP53 interaction inhibitors.", "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/221", "variant_origin": "Somatic", "pub_med_references": [ 26459177 ], "clinical_significance": "Resistance", "evidence_level": "B", "evidence_statement": "Phase I Trial of MDM2 inhibitor RG7112 in 116 patients with AML, ALL, CML, CLL, sCLL demonstrated sustained clinical improvement and induction of TP53 target genes in subset of patients with wild type TP53. No sustained clinical improvement or induction of TP53 target genes was observed in patients with mutant TP53.", "evidence_type": "Predictive", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/2966", "drugs": [ "RG7112" ], "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Leukemia", "rating": "3", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "1240" }, { "variant": "DELETERIOUS MUTATION", "variant_summary": "Deleterious mutations are mutations of TP53 with prior characterization demonstrating significant deleterious effect on TP53 protein function. Inactivating TP53 mutations prevent on target activity and efficacy of MDM2-TP53 interaction inhibitors.", "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/221", "variant_origin": "Somatic", "pub_med_references": [ 25730903 ], "clinical_significance": "Resistance", "evidence_level": "D", "evidence_statement": "MDM2 Inhibitor screen in a panel of 260 cancer cell lines with well characterized TP53 status shows that only cancer cell lines with unaltered TP53 may be sensitive to MDM2 Inhibitor AMGMDS3, while those with p53 mutations demonstrated resistance.", "evidence_type": "Predictive", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/2967", "drugs": [ "AMGMDS3" ], "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Cancer", "rating": "4", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "162" }, { "variant": "DELETERIOUS MUTATION", "variant_summary": "Deleterious mutations are mutations of TP53 with prior characterization demonstrating significant deleterious effect on TP53 protein function. Inactivating TP53 mutations prevent on target activity and efficacy of MDM2-TP53 interaction inhibitors.", "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/221", "variant_origin": "Somatic", "pub_med_references": [ 17671205 ], "clinical_significance": "Resistance", "evidence_level": "D", "evidence_statement": "MDM2 Inhibitor Nutlin-3a induced senescence in presence of functional TP53 in murine primary fibroblasts, oncogenically transformed fibroblasts, and fibrosarcoma cell lines. TP53 mutant cells lacking functional TP53 were completely insensitive to the drug.", "evidence_type": "Predictive", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/2968", "drugs": [ "Nutlin-3a" ], "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Cancer", "rating": "4", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "162" }, { "variant": "CONSERVED DOMAIN MUT", "variant_summary": "This conserved domain mutation variant covers mutations in regions of p53 reported to be highly conserved during evolution. These regions span codons 117-143 (region II), 171-181 (region III), 234-258 (region (IV), and 270-286 (region V). Region I covers approximately codons 10 through 25 but does not appear in all studies on conserved domain mutations. There is overlap with these regions and reported regions of hotspot p53 mutations, where it is observed that hotspots for detrimental mutation correspond to more highly evolutionary conserved regions. While there is agreement and overlap between different reports, the literature does not seem to indicate an exact consensus on these regions of human p53 at this time, but the four highly conserved regions are part of the DNA binding domain, and are reported to exist within codons 97 to 292.", "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/1300", "variant_origin": "Somatic", "pub_med_references": [ 11595686 ], "clinical_significance": "Poor Outcome", "evidence_level": "B", "evidence_statement": "Patients with conserved domain p53 mutation (n=61) were compared with those with wild type or non-conserved domain p53 mutation (n=117) in a cohort of 178 invasive ovarian carcinoma patients who had undergone surgery. Overall survival was decreased in the cohort with conserved domian mutation (p=0.005). Conserved domain mutation was an independent factor in univariate (but not multivariate) analysis of overall survival with relative risk 1.70 (1.17-2.47, p<0.007).", "evidence_type": "Prognostic", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/2993", "drugs": null, "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Ovarian Cancer", "rating": "3", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "2394" }, { "variant": "MUTATION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/222", "variant_origin": "Somatic", "pub_med_references": [ 28453411 ], "clinical_significance": null, "evidence_level": "B", "evidence_statement": "A pooled analysis to investigate the prognostic and predictive roles of TP53/KRAS and TP53/EGFR comutations (cm) in randomized trials of adjuvant chemotherapy compared to observational therapy encompassing a total of 3,553 patients. TP53/KRAS cm showed no prognostic effects but a borderline predictive effect (p=0,04) for negative effect of chemotherapy as compared to tp53/KRAS wt/wt. TP53/EGFR cm in was neither prognostic ( P = .83), nor significantly predictive ( P = .86). Similar results were observed for both groups for disease-free survival.", "evidence_type": "Prognostic", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/2999", "drugs": null, "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Lung Non-small Cell Carcinoma", "rating": "5", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "3908" }, { "variant": "OVEREXPRESSION", "variant_summary": null, "variant_civic_url": "https://civic.genome.wustl.edu/links/variants/1306", "variant_origin": "Somatic", "pub_med_references": [ 11595686 ], "clinical_significance": "Resistance", "evidence_level": "B", "evidence_statement": "In a study involving patients with invasive ovarian carcinoma who had undergone surgery, a subset of 73 patients were classified via response to platinum-based chemotherapy as sensitive or resistant/refractory and tested for p53 overexpression (>10% postive stained nuclei). 78% of p53 negative patients were classified as sensitive, in compariston to 39% of p53 positive patients (p=0.001).", "evidence_type": "Predictive", "evidence_status": "accepted", "evidence_direction": "Supports", "evidence_civic_url": "https://civic.genome.wustl.edu/links/evidence_items/3013", "drugs": [ "Cisplatin", "Carboplatin" ], "transcripts": null, "representative_transcript": "ENST00000269305.4", "disease": "Ovarian Cancer", "rating": "3", "gene": "TP53", "gene_civic_url": "https://civic.genome.wustl.edu/links/genes/45", "entrez_id": "7157", "doid": "2394" } ] }, "dbnsfp_genes": { "version": "v3_4", "items": [ { "kegg": { "id": [ "hsa04010", "hsa04110", "hsa04115", "hsa04210", "hsa04310", "hsa05030", "hsa05040", "hsa05210", "hsa05212", "hsa05213", "hsa05214", "hsa05215", "hsa05216", "hsa05217", "hsa05218", "hsa05219", "hsa05220", "hsa05222", "hsa05223" ], "full": [ "MAPK signaling pathway", "Cell cycle", "p53 signaling pathway", "Apoptosis", "Wnt signaling pathway", "Amyotrophic lateral sclerosis (ALS)", "Huntington's disease", "Colorectal cancer", "Pancreatic cancer", "Endometrial cancer", "Glioma", "Prostate cancer", "Thyroid cancer", "Basal cell carcinoma", "Melanoma", "Bladder cancer", "Chronic myeloid leukemia", "Small cell lung cancer", "Non-small cell lung cancer" ] }, "expressions_rpkm": { "whole_blood": 6.00388, "vagina": 12.7549, "uterus": 13.883500000000002, "thyroid": 10.382900000000001, "testis": 8.58473, "stomach": 8.701989999999999, "spleen": 16.9945, "small_intestine___terminal_ileum": 11.6496, "skin___sun_exposed__lower_leg": 20.445199999999996, "skin___not_sun_exposed__suprapubic": 20.111400000000003, "prostate": 11.778899999999998, "pituitary": 4.91742, "pancreas": 6.3052600000000005, "ovary": 16.2946, "nerve___tibial": 11.5291, "muscle___skeletal": 3.88969, "minor_salivary_gland": 11.3432, "brain___hypothalamus": 2.5338399999999996, "brain___hippocampus": 2.2206300000000003, "brain___frontal_cortex__ba9": 2.2682300000000004, "brain___cortex": 2.6111999999999997, "brain___cerebellum": 1.4009199999999997, "brain___cerebellar_hemisphere": 1.04868, "brain___caudate__basal_ganglia": 3.26298, "brain___anterior_cingulate_cortex__ba24": 2.50511, "brain___amygdala": 3.10035, "bladder": 14.246299999999998, "adipose___visceral__omentum": 9.99357, "adipose___subcutaneous": 12.0517, "adrenal_gland": 9.03215, "artery___aorta": 8.69709, "artery___coronary": 9.187259999999998, "artery___tibial": 9.10642, "brain___nucleus_accumbens__basal_ganglia": 2.73408, "brain___putamen__basal_ganglia": 2.84816, "brain___spinal_cord__cervicalc_1": 2.49533, "brain___substantia_nigra": 3.05483, "breast___mammary_tissue": 14.0185, "cells___ebv_transformed_lymphocytes": 38.38779999999999, "cells___transformed_fibroblasts": 14.0786, "cervix___ectocervix": 13.9891, "cervix___endocervix": 13.458, "colon___sigmoid": 7.76274, "colon___transverse": 11.9071, "esophagus___gastroesophageal_junction": 7.78288, "esophagus___mucosa": 14.6588, "esophagus___muscularis": 7.1133999999999995, "fallopian_tube": 14.1707, "heart___atrial_appendage": 4.47295, "heart___left_ventricle": 3.58802, "kidney___cortex": 7.37007, "liver": 5.52354, "lung": 9.20619 }, "gene_symbol": "TP53" } ] }, "exac_genes": { "version": "18_sep_2018", "items": [ { "prec": 0.08775030000000002, "pnull": 2.67186e-05, "pli": 0.912223, "syn_z": -0.042240200000000006, "mis_z": 1.37892, "cnv_score": -0.19665500000000002, "segdups": 0, "flag": false } ] }, "pub_med_articles": { "30146126": { "abstract": "Inherited bone-marrow-failure syndromes (IBMFSs) include heterogeneous genetic disorders characterized by bone-marrow failure, congenital anomalies, and an increased risk of malignancy. Many lines of evidence have suggested that p53 activation might be central to the pathogenesis of IBMFSs, including Diamond-Blackfan anemia (DBA) and dyskeratosis congenita (DC). However, the exact role of p53 activation in each clinical feature remains unknown. Here, we report unique de novo TP53 germline variants found in two individuals with an IBMFS accompanied by hypogammaglobulinemia, growth retardation, and microcephaly mimicking DBA and DC. TP53 is a tumor-suppressor gene most frequently mutated in human cancers, and occasional germline variants occur in Li-Fraumeni cancer-predisposition syndrome. Most of these mutations affect the core DNA-binding domain, leading to compromised transcriptional activities. In contrast, the variants found in the two individuals studied here caused the same truncation of the protein, resulting in the loss of 32 residues from the C-terminal domain (CTD). Unexpectedly, the p53 mutant had augmented transcriptional activities, an observation not previously described in humans. When we expressed this mutant in zebrafish and human-induced pluripotent stem cells, we observed impaired erythrocyte production. These findings together with close similarities to published knock-in mouse models of TP53 lacking the CTD demonstrate that the CTD-truncation mutations of TP53 cause IBMFS, providing important insights into the previously postulated connection between p53 and IBMFSs.", "authors": [ "Toki, T", "Yoshida, K", "Wang, R", "Nakamura, S", "Maekawa, T", "Goi, K", "Katoh, MC", "Mizuno, S", "Sugiyama, F", "Kanezaki, R", "Uechi, T", "Nakajima, Y", "Sato, Y", "Okuno, Y", "Sato-Otsubo, A", "Shiozawa, Y", "Kataoka, K", "Shiraishi, Y", "Sanada, M", "Chiba, K", "Tanaka, H", "Terui, K", "Sato, T", "Kamio, T", "Sakaguchi, H", "Ohga, S", "Kuramitsu, M", "Hamaguchi, I", "Ohara, A", "Kanno, H", "Miyano, S", "Kojima, S", "Ishiguro, A", "Sugita, K", "Kenmochi, N", "Takahashi, S", "Eto, K", "Ogawa, S", "Ito, E" ], "is_common_article": false, "date_published": 20180906, "date_completed": 0, "format": "Article", "pub_med_id": 30146126, "title": "De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome.", "journal": "American journal of human genetics", "journal_abbreviation": "Am. J. Hum. Genet.", "journal_issue": "volume:103, issue:3" }, "27967292": { "abstract": "TP53 gene mutations occurring in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are associated with high-risk karyotypes including 17p abnormalities, monosomal and complex cytogenetics. TP53 mutations in these disorders portend rapid disease progression and resistance to conventional therapeutics. Notably, the size of the TP53 mutant clone as measured by mutation allele burden is directly linked to overall survival (OS) confirming the importance of p53 as a negative prognostic variable. In nucleolar stress-induced ribosomopathies, such as del(5q) MDS, disassociation of MDM2 and p53 results in p53 accumulation in erythroid precursors manifested as erythroid hypoplasia. P53 antagonism by lenalidomide or other therapeutics such as antisense oligonucleotides, repopulates erythroid precursors and enhances effective erythropoiesis. These findings demonstrate that p53 is an intriguing therapeutic target that is currently under investigation in MDS and AML. This study reviews molecular advances in understanding the role of p53 in MDS and AML, and explores potential therapeutic strategies in this era of personalized medicine.", "authors": [ "Zhang, L", "McGraw, KL", "Sallman, DA", "List, AF" ], "is_common_article": false, "date_published": 20170800, "date_completed": 20180112, "format": "Article", "pub_med_id": 27967292, "title": "The role of p53 in myelodysplastic syndromes and acute myeloid leukemia: molecular aspects and clinical implications.", "journal": "Leukemia & lymphoma", "journal_abbreviation": "Leuk. Lymphoma", "journal_issue": "volume:58, issue:8" }, "27601546": { "abstract": "PURPOSE\nThe genetic basis of myelodysplastic syndromes (MDS) is heterogeneous, and various combinations of somatic mutations are associated with different clinical phenotypes and outcomes. Whether the genetic basis of MDS influences the outcome of allogeneic hematopoietic stem-cell transplantation (HSCT) is unclear.\n\nPATIENTS AND METHODS\nWe studied 401 patients with MDS or acute myeloid leukemia (AML) evolving from MDS (MDS/AML). We used massively parallel sequencing to examine tumor samples collected before HSCT for somatic mutations in 34 recurrently mutated genes in myeloid neoplasms. We then analyzed the impact of mutations on the outcome of HSCT.\n\nRESULTS\nOverall, 87% of patients carried one or more oncogenic mutations. Somatic mutations of ASXL1, RUNX1, and TP53 were independent predictors of relapse and overall survival after HSCT in both patients with MDS and patients with MDS/AML (P values ranging from .003 to .035). In patients with MDS/AML, gene ontology (ie, secondary-type AML carrying mutations in genes of RNA splicing machinery, TP53-mutated AML, or de novo AML) was an independent predictor of posttransplantation outcome (P = .013). The impact of ASXL1, RUNX1, and TP53 mutations on posttransplantation survival was independent of the revised International Prognostic Scoring System (IPSS-R). Combining somatic mutations and IPSS-R risk improved the ability to stratify patients by capturing more prognostic information at an individual level. Accounting for various combinations of IPSS-R risk and somatic mutations, the 5-year probability of survival after HSCT ranged from 0% to 73%.\n\nCONCLUSION\nSomatic mutation in ASXL1, RUNX1, or TP53 is independently associated with unfavorable outcomes and shorter survival after allogeneic HSCT for patients with MDS and MDS/AML. Accounting for these genetic lesions may improve the prognostication precision in clinical practice and in designing clinical trials.", "authors": [ "Della Porta, MG", "Gallì, A", "Bacigalupo, A", "Zibellini, S", "Bernardi, M", "Rizzo, E", "Allione, B", "van Lint, MT", "Pioltelli, P", "Marenco, P", "Bosi, A", "Voso, MT", "Sica, S", "Cuzzola, M", "Angelucci, E", "Rossi, M", "Ubezio, M", "Malovini, A", "Limongelli, I", "Ferretti, VV", "Spinelli, O", "Tresoldi, C", "Pozzi, S", "Luchetti, S", "Pezzetti, L", "Catricalà, S", "Milanesi, C", "Riva, A", "Bruno, B", "Ciceri, F", "Bonifazi, F", "Bellazzi, R", "Papaemmanuil, E", "Santoro, A", "Alessandrino, EP", "Rambaldi, A", "Cazzola, M" ], "is_common_article": false, "date_published": 20161020, "date_completed": 0, "format": "Article", "pub_med_id": 27601546, "title": "Clinical Effects of Driver Somatic Mutations on the Outcomes of Patients With Myelodysplastic Syndromes Treated With Allogeneic Hematopoietic Stem-Cell Transplantation.", "journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", "journal_abbreviation": "J. Clin. Oncol.", "journal_issue": "volume:34, issue:30" }, "27050224": { "authors": [ "Zhang, J", "Nichols, KE", "Downing, JR" ], "is_common_article": false, "date_published": 20160407, "date_completed": 20160407, "format": "Article", "pub_med_id": 27050224, "title": "Germline Mutations in Predisposition Genes in Pediatric Cancer.", "journal": "The New England journal of medicine", "journal_abbreviation": "N. Engl. J. Med.", "journal_issue": "volume:374, issue:14" }, "26899019": { "abstract": "INTRODUCTION\nTumor protein p53 gene (TP53) mutations are common in stage I through III non-small cell lung cancer, but clinical trials have shown inconsistent results regarding their relationship to the effects of adjuvant therapy. The objective is to clarify their putative prognostic and predictive effects.\n\nMETHODS\nA pooled analysis of TP53 mutations (exons 5-8) was conducted in four randomized trials (the International Adjuvant Lung Cancer Trial, J BRonchus 10, Cancer and Leukemia Group B-9633, and Adjuvant Navelbine International Trialist Association trial) of platinum-based adjuvant chemotherapy (ACT) versus observation (OBS). Hazard ratios (HRs) and 95% confidence intervals (CIs) of mutant versus wild-type (WT) TP53 for overall survival (OS) and disease-free survival (DFS) were estimated using a multivariable Cox model stratified on trial and adjusted on sex, age, and clinicopathological variables. Predictive value was evaluated with an interaction between treatment and TP53.\n\nRESULTS\nA total of 1209 patients (median follow-up 5.5 years) were included. There were 573 deaths (47%) and 653 DFS events (54%). Mutations (434 [36%]) had no prognostic effect (OBS HROS = 0.99, 95% CI: 0.77-1.28, p = 0.95; HRDFS = 0.99, 95% CI: 0.78-1.25, p = 0.92) but were marginally predictive of benefit from ACT for OS (test for interaction: OS, p = 0.06; DFS, p = 0.11). Patients with WT TP53 had a tendency toward better outcomes with ACT than did those in the OBS group (HROS = 0.77, 95% CI: 0.62-0.95, p = 0.02; HRDFS = 0.75, 95% CI: 0.62-0.92, p = 0.005). In the ACT arm, a deleterious effect of mutant versus WT TP53 was observed (HROS = 1.40, 95% CI: 1.10-1.78, p = 0.006; HRDFS = 1.31, 95% CI: 1.04-1.64, p = 0.02).\n\nCONCLUSIONS\nTP53 mutation had no prognostic effect but was marginally predictive for survival from ACT. In patients who received ACT, TP53 mutation tended to be associated with shorter survival than wild-type TP53.", "authors": [ "Ma, X", "Le Teuff, G", "Lacas, B", "Tsao, MS", "Graziano, S", "Pignon, JP", "Douillard, JY", "Le Chevalier, T", "Seymour, L", "Filipits, M", "Pirker, R", "Jänne, PA", "Shepherd, FA", "Brambilla, E", "Soria, JC", "Hainaut, P" ], "is_common_article": false, "date_published": 20160600, "date_completed": 0, "format": "Article", "pub_med_id": 26899019, "title": "Prognostic and Predictive Effect of TP53 Mutations in Patients with Non-Small Cell Lung Cancer from Adjuvant Cisplatin-Based Therapy Randomized Trials: A LACE-Bio Pooled Analysis.", "journal": "Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer", "journal_abbreviation": "J Thorac Oncol", "journal_issue": "volume:11, issue:6" }, "26837699": { "abstract": "Genomic studies have revealed the complex clonal heterogeneity of chronic lymphocytic leukemia (CLL). The acquisition and selection of genomic aberrations may be critical to understanding the progression of this disease. In this study, we have extensively characterized the mutational status of TP53, SF3B1, BIRC3, NOTCH1, and ATM in 406 untreated CLL cases by ultra-deep next-generation sequencing, which detected subclonal mutations down to 0.3% allele frequency. Clonal dynamics were examined in longitudinal samples of 48 CLL patients. We identified a high proportion of subclonal mutations, isolated or associated with clonal aberrations. TP53 mutations were present in 10.6% of patients (6.4% clonal, 4.2% subclonal), ATM mutations in 11.1% (7.8% clonal, 1.3% subclonal, 2% germ line mutations considered pathogenic), SF3B1 mutations in 12.6% (7.4% clonal, 5.2% subclonal), NOTCH1 mutations in 21.8% (14.2% clonal, 7.6% subclonal), and BIRC3 mutations in 4.2% (2% clonal, 2.2% subclonal). ATM mutations, clonal SF3B1, and both clonal and subclonal NOTCH1 mutations predicted for shorter time to first treatment irrespective of the immunoglobulin heavy-chain variable-region gene (IGHV) mutational status. Clonal and subclonal TP53 and clonal NOTCH1 mutations predicted for shorter overall survival together with the IGHV mutational status. Clonal evolution in longitudinal samples mainly occurred in cases with mutations in the initial samples and was observed not only after chemotherapy but also in untreated patients. These findings suggest that the characterization of the subclonal architecture and its dynamics in the evolution of the disease may be relevant for the management of CLL patients.", "authors": [ "Nadeu, F", "Delgado, J", "Royo, C", "Baumann, T", "Stankovic, T", "Pinyol, M", "Jares, P", "Navarro, A", "Martín-García, D", "Beà, S", "Salaverria, I", "Oldreive, C", "Aymerich, M", "Suárez-Cisneros, H", "Rozman, M", "Villamor, N", "Colomer, D", "López-Guillermo, A", "González, M", "Alcoceba, M", "Terol, MJ", "Colado, E", "Puente, XS", "López-Otín, C", "Enjuanes, A", "Campo, E" ], "is_common_article": false, "date_published": 20160428, "date_completed": 20170713, "format": "Article", "pub_med_id": 26837699, "title": "Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia.", "journal": "Blood", "journal_abbreviation": "Blood", "journal_issue": "volume:127, issue:17" }, "26771088": { "abstract": "Treatment success in patients with acute myeloid leukaemia (AML) is heterogeneous. Cytogenetic and molecular alterations are strong prognostic factors, which have been used to individualize treatment. Here, we studied the impact of TP53 mutations on the outcome of AML patients with adverse cytogenetic risk treated with allogeneic haematopoietic stem cell transplantation (HSCT). Samples of 97 patients with AML and adverse-risk cytogenetics who had received a HSCT within three randomized trials were analysed. Complete sequencing of the TP53 coding region was performed using next generation sequencing. The median age was 51 years. Overall, TP53 mutations were found in 40 patients (41%). With a median follow up of 67 months, the three-year probabilities of overall survival (OS) and event-free survival for patients with TP53 wild type were 33% [95% confidence interval (CI), 21% to 45%] and 24% (95% CI, 13% to 35%) compared to 10% (95% CI, 0% to 19%) and 8% (95% CI, 0% to 16%) (P = 0·002 and P = 0·007) for those with mutated TP53, respectively. In multivariate analysis, the TP53-mutation status had a negative impact on OS (Hazard Ratio = 1·7; P = 0·066). Mutational analysis of TP53 might be an important additional tool to predict outcome after HSCT in patients with adverse karyotype AML.", "authors": [ "Middeke, JM", "Herold, S", "Rücker-Braun, E", "Berdel, WE", "Stelljes, M", "Kaufmann, M", "Schäfer-Eckart, K", "Baldus, CD", "Stuhlmann, R", "Ho, AD", "Einsele, H", "Rösler, W", "Serve, H", "Hänel, M", "Sohlbach, K", "Klesse, C", "Mohr, B", "Heidenreich, F", "Stölzel, F", "Röllig, C", "Platzbecker, U", "Ehninger, G", "Bornhäuser, M", "Thiede, C", "Schetelig, J" ], "is_common_article": false, "date_published": 20160300, "date_completed": 20160718, "format": "Article", "pub_med_id": 26771088, "title": "TP53 mutation in patients with high-risk acute myeloid leukaemia treated with allogeneic haematopoietic stem cell transplantation.", "journal": "British journal of haematology", "journal_abbreviation": "Br. J. Haematol.", "journal_issue": "volume:172, issue:6" }, "26695660": { "abstract": "Developing patient derived models from individual tumors that capture the biological heterogeneity and mutation landscape in advanced prostate cancer is challenging, but essential for understanding tumor progression and delivery of personalized therapy in metastatic castrate resistant prostate cancer stage. To demonstrate the feasibility of developing patient derived xenograft models in this stage, we present a case study wherein xenografts were derived from cancer metastases in a patient progressing on androgen deprivation therapy and prior to initiating pre-chemotherapy enzalutamide treatment. Tissue biopsies from a metastatic rib lesion were obtained for sequencing before and after initiating enzalutamide treatment over a twelve-week period and also implanted subcutaneously as well as under the renal capsule in immuno-deficient mice. The genome and transcriptome landscapes of xenografts and the original patient tumor tissues were compared by performing whole exome and transcriptome sequencing of the metastatic tumor tissues and the xenografts at both time points. After comparing the somatic mutations, copy number variations, gene fusions and gene expression we found that the patient's genomic and transcriptomic alterations were preserved in the patient derived xenografts with high fidelity. These xenograft models provide an opportunity for predicting efficacy of existing and potentially novel drugs that is based on individual metastatic tumor expression signature and molecular pharmacology for delivery of precision medicine.", "authors": [ "Kohli, M", "Wang, L", "Xie, F", "Sicotte, H", "Yin, P", "Dehm, SM", "Hart, SN", "Vedell, PT", "Barman, P", "Qin, R", "Mahoney, DW", "Carlson, RE", "Eckel-Passow, JE", "Atwell, TD", "Eiken, PW", "McMenomy, BP", "Wieben, ED", "Jha, G", "Jimenez, RE", "Weinshilboum, R", "Wang, L" ], "is_common_article": false, "date_published": 20150000, "date_completed": 20160624, "format": "Article", "pub_med_id": 26695660, "title": "Mutational Landscapes of Sequential Prostate Metastases and Matched Patient Derived Xenografts during Enzalutamide Therapy.", "journal": "PloS one", "journal_abbreviation": "PLoS ONE", "journal_issue": "volume:10, issue:12" }, "26646755": { "abstract": "BACKGROUND\nTo investigate whether TP53 DNA mutational status impacts progression-free survival (PFS) in patients with advanced sarcomas (soft tissue sarcoma) treated with vascular endothelial growth factor receptors (VEGFR) inhibition.\n\nPATIENTS AND METHODS\nWe retrospectively reviewed 19 cases of patients treated at the Ohio State James Comprehensive Cancer Center with advanced sarcoma treated with VEGFR inhibition who also had next-generation sequencing of their tumors (via FoundationOne Heme panel). We evaluated TP53 as well as mutations that were observed in at least 20% of patients and evaluated its contribution to PFS using the Kaplan-Meier survival analysis of available radiology end points.\n\nRESULTS\nMutations that were observed in at least 20% of patients included TP53 and Rb1. Only TP53 was predictive of PFS in the context of VEGFR inhibition. The PFS of patients with TP53 mutations was significantly greater than TP53 wild-type tumors with the median PFS of 208 versus 136 days, respectively [P = 0.036, hazards ratio 0.38 (95% confidence interval 0.09-0.83)].\n\nCONCLUSIONS\nMutations in TP53 may serve as a predictive biomarker of response to VEGFR inhibition in patients with advanced sarcoma. Larger, prospective studies are necessary to confirm these findings.", "authors": [ "Koehler, K", "Liebner, D", "Chen, JL" ], "is_common_article": false, "date_published": 20160300, "date_completed": 20161213, "format": "Article", "pub_med_id": 26646755, "title": "TP53 mutational status is predictive of pazopanib response in advanced sarcomas.", "journal": "Annals of oncology : official journal of the European Society for Medical Oncology", "journal_abbreviation": "Ann. Oncol.", "journal_issue": "volume:27, issue:3" }, "26618142": { "abstract": "The functional importance of p53 as a tumor suppressor gene is evident through its pervasiveness in cancer biology. The p53 gene is the most commonly altered gene in human cancer; however, not all genetic alterations are biologically equivalent. The majority of alterations involve p53 missense mutations that result in the production of mutant p53 proteins. Such mutant p53 proteins lack normal p53 function and may concomitantly gain novel functions, often with deleterious effects. Here, we review characterized mechanisms of mutant p53 gain of function in various model systems. In addition, we review mutant p53 addiction as emerging evidence suggests that tumors may depend on sustained mutant p53 activity for continued growth. We also discuss the role of p53 in stromal elements and their contribution to tumor initiation and progression. Lastly, current genetic mouse models of mutant p53 in various organ systems are reviewed and their limitations discussed.", "authors": [ "Kim, MP", "Zhang, Y", "Lozano, G" ], "is_common_article": false, "date_published": 20150000, "date_completed": 20151130, "format": "Article", "pub_med_id": 26618142, "title": "Mutant p53: Multiple Mechanisms Define Biologic Activity in Cancer.", "journal": "Frontiers in oncology", "journal_abbreviation": "Front Oncol", "journal_issue": "volume:5" }, "26459177": { "abstract": "PURPOSE\nRG7112 is a small-molecule MDM2 antagonist. MDM2 is a negative regulator of the tumor suppressor p53 and frequently overexpressed in leukemias. Thus, a phase I study of RG7112 in patients with hematologic malignancies was conducted.\n\nEXPERIMENTAL DESIGN\nPrimary study objectives included determination of the dose and safety profile of RG7112. Secondary objectives included evaluation of pharmacokinetics; pharmacodynamics, such as TP53-mutation status and MDM2 expression; and preliminary clinical activity. Patients were divided into two cohorts: Stratum A [relapsed/refractory acute myeloid leukemia (AML; except acute promyelocytic leukemia), acute lymphoblastic leukemia, and chronic myelogenous leukemia] and Stratum B (relapsed/refractory chronic lymphocytic leukemia/small cell lymphocytic leukemia; CLL/sCLL). Some Stratum A patients were treated at the MTD to assess clinical activity.\n\nRESULTS\nRG7112 was administered to 116 patients (96 patients in Stratum A and 20 patients in Stratum B). All patients experienced at least 1 adverse event, and 3 dose-limiting toxicities were reported. Pharmacokinetic analysis indicated that twice-daily dosing enhanced daily exposure. Antileukemia activity was observed in the 30 patients with AML assessed at the MTD, including 5 patients who met International Working Group (IWG) criteria for response. Exploratory analysis revealed TP53 mutations in 14% of Stratum A patients and in 40% of Stratum B patients. Two patients with TP53 mutations exhibited clinical activity. p53 target genes were induced only in TP53 wild-type leukemic cells. Baseline expression levels of MDM2 correlated positively with clinical response.\n\nCONCLUSIONS\nRG7112 demonstrated clinical activity against relapsed/refractory AML and CLL/sCLL. MDM2 inhibition resulted in p53 stabilization and transcriptional activation of p53-target genes. We provide proof-of-concept that MDM2 inhibition restores p53 function and generates clinical responses in hematologic malignancies.", "authors": [ "Andreeff, M", "Kelly, KR", "Yee, K", "Assouline, S", "Strair, R", "Popplewell, L", "Bowen, D", "Martinelli, G", "Drummond, MW", "Vyas, P", "Kirschbaum, M", "Iyer, SP", "Ruvolo, V", "González, GM", "Huang, X", "Chen, G", "Graves, B", "Blotner, S", "Bridge, P", "Jukofsky, L", "Middleton, S", "Reckner, M", "Rueger, R", "Zhi, J", "Nichols, G", "Kojima, K" ], "is_common_article": false, "date_published": 20160215, "date_completed": 20161103, "format": "Article", "pub_med_id": 26459177, "title": "Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia.", "journal": "Clinical cancer research : an official journal of the American Association for Cancer Research", "journal_abbreviation": "Clin. Cancer Res.", "journal_issue": "volume:22, issue:4" }, "28453411": { "abstract": "Purpose Our previous work evaluated individual prognostic and predictive roles of TP53, KRAS, and EGFR in non-small-cell lung cancer (NSCLC). In this analysis, we explore the prognostic and predictive roles of TP53/KRAS and TP53/EGFR comutations in randomized trials of adjuvant chemotherapy versus observation. Patients and Methods Mutation analyses (wild-type [WT] and mutant) for TP53, KRAS, and EGFR were determined in blinded fashion in multiple laboratories. Primary and secondary end points of pooled analysis were overall survival and disease-free survival. We evaluated the role of TP53/KRAS comutation in all patients and in the adenocarcinoma subgroup as well as the TP53/EGFR comutation in adenocarcinoma only through a multivariable Cox proportional hazards model stratified by trial. Results Of 3,533 patients with NSCLC, 1,181 (557 deaths) and 404 (170 deaths) were used for TP53/KRAS and TP53/EGFR analyses. For TP53/KRAS mutation status, no prognostic effect was observed ( P = .61), whereas a borderline predictive effect ( P = .04) was observed with a deleterious effect of chemotherapy with TP53/KRAS comutations versus WT/WT (hazard ratio, 2.49 [95% CI, 1.10 to 5.64]; P = .03). TP53/EGFR comutation in adenocarcinoma was neither prognostic ( P = .83), nor significantly predictive ( P = .86). Similar results were observed for both groups for disease-free survival. Conclusion We could identify no prognostic effect of the KRAS or EGFR driver and TP53 tumor suppressor comutation. Our observation of a potential negative predictive effect of TP53/KRAS comutation requires validation.", "authors": [ "Shepherd, FA", "Lacas, B", "Le Teuff, G", "Hainaut, P", "Jänne, PA", "Pignon, JP", "Le Chevalier, T", "Seymour, L", "Douillard, JY", "Graziano, S", "Brambilla, E", "Pirker, R", "Filipits, M", "Kratzke, R", "Soria, JC", "Tsao, MS" ], "is_common_article": false, "date_published": 20170620, "date_completed": 20170829, "format": "Article", "pub_med_id": 28453411, "title": "Pooled Analysis of the Prognostic and Predictive Effects of TP53 Comutation Status Combined With KRAS or EGFR Mutation in Early-Stage Resected Non-Small-Cell Lung Cancer in Four Trials of Adjuvant Chemotherapy.", "journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", "journal_abbreviation": "J. Clin. Oncol.", "journal_issue": "volume:35, issue:18" }, "25730903": { "abstract": "Previous reports have provided evidence that p53 mutation is a strong negative predictor of response to MDM2 inhibitors. However, this correlation is not absolute, as many p53Mutant cell lines have been reported to respond to MDM2 inhibition, while many p53WT cell lines have been shown not to respond. To better understand the nature of these exceptions, we screened a panel of 260 cell lines and noted similar discrepancies. However, upon extensive curation of this panel, these apparent exceptions could be eliminated, revealing a perfect correlation between p53 mutational status and MDM2 inhibitor responsiveness. It has been suggested that the MDM2-amplified subset of p53WT tumors might be particularly sensitive to MDM2 inhibition. To facilitate clinical testing of this hypothesis, we identified a rationally derived copy number cutoff for assignment of functionally relevant MDM2 amplification. Applying this cutoff resulted in a pan-cancer MDM2 amplification rate far lower than previously published.", "authors": [ "Saiki, AY", "Caenepeel, S", "Cosgrove, E", "Su, C", "Boedigheimer, M", "Oliner, JD" ], "is_common_article": false, "date_published": 20150410, "date_completed": 20160526, "format": "Article", "pub_med_id": 25730903, "title": "Identifying the determinants of response to MDM2 inhibition.", "journal": "Oncotarget", "journal_abbreviation": "Oncotarget", "journal_issue": "volume:6, issue:10" }, "24957073": { "abstract": "In this updated analysis of the EXPERT-C trial we show that, in magnetic resonance imaging-defined, high-risk, locally advanced rectal cancer, adding cetuximab to a treatment strategy with neoadjuvant CAPOX followed by chemoradiotherapy, surgery, and adjuvant CAPOX is not associated with a statistically significant improvement in progression-free survival (PFS) and overall survival (OS) in both KRAS/BRAF wild-type and unselected patients. In a retrospective biomarker analysis, TP53 was not prognostic but emerged as an independent predictive biomarker for cetuximab benefit. After a median follow-up of 65.0 months, TP53 wild-type patients (n = 69) who received cetuximab had a statistically significant better PFS (89.3% vs 65.0% at 5 years; hazard ratio [HR] = 0.23; 95% confidence interval [CI] = 0.07 to 0.78; two-sided P = .02 by Cox regression) and OS (92.7% vs 67.5% at 5 years; HR = 0.16; 95% CI = 0.04 to 0.70; two-sided P = .02 by Cox regression) than TP53 wild-type patients who were treated in the control arm. An interaction between TP53 status and cetuximab effect was found (P < .05) and remained statistically significant after adjusting for statistically significant prognostic factors and KRAS.", "authors": [ "Sclafani, F", "Gonzalez, D", "Cunningham, D", "Hulkki Wilson, S", "Peckitt, C", "Tabernero, J", "Glimelius, B", "Cervantes, A", "Dewdney, A", "Wotherspoon, A", "Brown, G", "Tait, D", "Oates, J", "Chau, I" ], "is_common_article": false, "date_published": 20140700, "date_completed": 20140811, "format": "Article", "pub_med_id": 24957073, "title": "TP53 mutational status and cetuximab benefit in rectal cancer: 5-year results of the EXPERT-C trial.", "journal": "Journal of the National Cancer Institute", "journal_abbreviation": "J. Natl. Cancer Inst.", "journal_issue": "volume:106, issue:7" }, "24943832": { "abstract": "Through the European Research Initiative on chronic lymphocytic leukemia (CLL) (ERIC), we screened 3490 patients with CLL for mutations within the NOTCH1 (n=3334), SF3B1 (n=2322), TP53 (n=2309), MYD88 (n=1080) and BIRC3 (n=919) genes, mainly at diagnosis (75%) and before treatment (>90%). BIRC3 mutations (2.5%) were associated with unmutated IGHV genes (U-CLL), del(11q) and trisomy 12, whereas MYD88 mutations (2.2%) were exclusively found among M-CLL. NOTCH1, SF3B1 and TP53 exhibited variable frequencies and were mostly enriched within clinically aggressive cases. Interestingly, as the timespan between diagnosis and mutational screening increased, so too did the incidence of SF3B1 mutations; no such increase was observed for NOTCH1 mutations. Regarding the clinical impact, NOTCH1 mutations, SF3B1 mutations and TP53 aberrations (deletion/mutation, TP53ab) correlated with shorter time-to-first-treatment (P<0.0001) in 889 treatment-naive Binet stage A cases. In multivariate analysis (n=774), SF3B1 mutations and TP53ab along with del(11q) and U-CLL, but not NOTCH1 mutations, retained independent significance. Importantly, TP53ab and SF3B1 mutations had an adverse impact even in U-CLL. In conclusion, we support the clinical relevance of novel recurrent mutations in CLL, highlighting the adverse impact of SF3B1 and TP53 mutations, even independent of IGHV mutational status, thus underscoring the need for urgent standardization/harmonization of the detection methods.", "authors": [ "Baliakas, P", "Hadzidimitriou, A", "Sutton, LA", "Rossi, D", "Minga, E", "Villamor, N", "Larrayoz, M", "Kminkova, J", "Agathangelidis, A", "Davis, Z", "Tausch, E", "Stalika, E", "Kantorova, B", "Mansouri, L", "Scarfò, L", "Cortese, D", "Navrkalova, V", "Rose-Zerilli, MJ", "Smedby, KE", "Juliusson, G", "Anagnostopoulos, A", "Makris, AM", "Navarro, A", "Delgado, J", "Oscier, D", "Belessi, C", "Stilgenbauer, S", "Ghia, P", "Pospisilova, S", "Gaidano, G", "Campo, E", "Strefford, JC", "Stamatopoulos, K", "Rosenquist, R" ], "is_common_article": false, "date_published": 20150200, "date_completed": 20150406, "format": "Article", "pub_med_id": 24943832, "title": "Recurrent mutations refine prognosis in chronic lymphocytic leukemia.", "journal": "Leukemia", "journal_abbreviation": "Leukemia", "journal_issue": "volume:29, issue:2" }, "27959731": { "abstract": "BACKGROUND\nThe molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear.\n\nMETHODS\nWe enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols.\n\nRESULTS\nOf the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles.\n\nCONCLUSIONS\nPatients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT01687400 .).", "authors": [ "Welch, JS", "Petti, AA", "Miller, CA", "Fronick, CC", "O'Laughlin, M", "Fulton, RS", "Wilson, RK", "Baty, JD", "Duncavage, EJ", "Tandon, B", "Lee, YS", "Wartman, LD", "Uy, GL", "Ghobadi, A", "Tomasson, MH", "Pusic, I", "Romee, R", "Fehniger, TA", "Stockerl-Goldstein, KE", "Vij, R", "Oh, ST", "Abboud, CN", "Cashen, AF", "Schroeder, MA", "Jacoby, MA", "Heath, SE", "Luber, K", "Janke, MR", "Hantel, A", "Khan, N", "Sukhanova, MJ", "Knoebel, RW", "Stock, W", "Graubert, TA", "Walter, MJ", "Westervelt, P", "Link, DC", "DiPersio, JF", "Ley, TJ" ], "is_common_article": false, "date_published": 20161124, "date_completed": 20161226, "format": "Article", "pub_med_id": 27959731, "title": "TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes.", "journal": "The New England journal of medicine", "journal_abbreviation": "N. Engl. J. Med.", "journal_issue": "volume:375, issue:21" }, "24836762": { "abstract": "TP53 mutations are found in 5-10% of MDS and AML, where they are generally associated with complex karyotype and an overall poor prognosis. However, the impact of TP53 mutations in MDS treated with azacitidine (AZA) remains unclear. We analyzed TP53 mutations in 62 patients with high risk MDS or AML treated with AZA. A TP53 mutation was found in 23 patients (37.1%), associated with complex karyotype in 18 (78.3%) of them. TP53 mutations had no significant impact on response or complete response to AZA (p=0.60 and p=0.26, respectively). By univariate analysis, OS was negatively influenced by the presence of TP53 mutation (median OS 12.4 months versus 23.7 months, p<10(-4)), abnormal cytogenetics (median OS 14.4 months vs 33 months, p=0.02) complex cytogenetics (median OS 12.7 months versus 23.7 months, p=0.0005), and a diagnosis of AML (median 14.5 months vs 21.2 months for MDS or CMML, p=0.02). By multivariate analysis, only TP53 mutational status (HR 2.89 (95% confidence interval 1.38-6.04; p=0.005) retained statistical significance for OS. Results were similar when the analysis was restricted to MDS and CMML patients, excluding AML (HR=2.46 (95% confidence interval: 1.1-6.4); p=0.04)). Thus, TP53 mutations strongly correlated with poorer survival in higher risk MDS and AML treated with AZA.", "authors": [ "Bally, C", "Adès, L", "Renneville, A", "Sebert, M", "Eclache, V", "Preudhomme, C", "Mozziconacci, MJ", "de The, H", "Lehmann-Che, J", "Fenaux, P" ], "is_common_article": false, "date_published": 20140700, "date_completed": 20140801, "format": "Article", "pub_med_id": 24836762, "title": "Prognostic value of TP53 gene mutations in myelodysplastic syndromes and acute myeloid leukemia treated with azacitidine.", "journal": "Leukemia research", "journal_abbreviation": "Leuk. Res.", "journal_issue": "volume:38, issue:7" }, "29296692": { "abstract": "Polycythemia vera (PV) is characterized by JAK2 and essential thrombocythemia (ET) by JAK2 , calreticulin ( CALR ), and myeloproliferative leukemia virus oncogene ( MPL ) mutations; we describe the occurrence and prognostic relevance of DNA sequence variants/mutations other than JAK2 / CALR / MPL . A myeloid neoplasm-relevant 27-gene panel was used for next-generation sequencing of bone marrow or whole blood DNA and conventional tools were used for analysis. \"Adverse variants/mutations\" were identified by age-adjusted multivariable analysis of impact on overall, leukemia-free, or myelofibrosis-free survival. Fifty-three percent of 133 Mayo Clinic patients with PV and 53% of 183 with ET harbored 1 or more sequence variants/mutations other than JAK2 / CALR/MPL ; the most frequent were TET2 and ASXL1 . \"Adverse variants/mutations\" in PV included ASXL1 , SRSF2 , and IDH2 and in ET SH2B3 , SF3B1 , U2AF1 , TP53 , IDH2 , and EZH2 ; combined prevalence was 15% and 15%, respectively. Adverse variants/mutations were associated with inferior survival in both PV (median, 7.7 vs 16.9 years) and ET (median, 9 vs 22 years) and the effect was independent of conventional prognostic models with respective hazard ratio (95% confidence interval) of 2.8 (1.5-5.1) and 2.6 (1.4-4.8); these observations were validated in 215 Italian patients with PV and 174 with ET. In both Mayo Clinic and Italian cohorts, leukemic or fibrotic progression was also predicted by adverse variants/mutations. Number of mutations did not provide additional prognostic information. We conclude that targeted deep sequencing in PV and ET allows for genetic risk stratification that is independent of clinically derived prognostic models.", "authors": [ "Tefferi, A", "Lasho, TL", "Guglielmelli, P", "Finke, CM", "Rotunno, G", "Elala, Y", "Pacilli, A", "Hanson, CA", "Pancrazzi, A", "Ketterling, RP", "Mannarelli, C", "Barraco, D", "Fanelli, T", "Pardanani, A", "Gangat, N", "Vannucchi, AM" ], "is_common_article": false, "date_published": 20161129, "date_completed": 0, "format": "Article", "pub_med_id": 29296692, "title": "Targeted deep sequencing in polycythemia vera and essential thrombocythemia.", "journal": "Blood advances", "journal_abbreviation": "Blood Adv", "journal_issue": "volume:1, issue:1" }, "24740294": { "abstract": "BACKGROUND\nPrevious studies have yielded conflicting results regarding the relationship between p53 status and response to chemotherapy in patients with gastric cancer. We therefore performed a meta-analysis to expound the relationship between p53 status and response to chemotherapy.\n\nMETHODS/FINDINGS\nThirteen previously published eligible studies, including 564 cases, were identified and included in this meta-analysis. p53 positive status (high expression of p53 protein and/or a mutant p53 gene) was associated with improved response in gastric cancer patients who received chemotherapy (good response: risk ratio [RR] = 0.704; 95% confidence intervals [CI] = 0.550-0.903; P = 0.006). In further stratified analyses, association with a good response remained in the East Asian population (RR = 0.657; 95% CI = 0.488-0.884; P = 0.005), while in the European subgroup, patients with p53 positive status tended to have a good response to chemotherapy, although this did not reach statistical significance (RR = 0.828, 95% CI = 0.525-1.305; P = 0.417). As five studies used neoadjuvant chemotherapy (NCT) and one used neoadjuvant chemoradiotherapy (NCRT), we also analyzed these data, and found that p53 positive status was associated with a good response in gastric cancer patients who received chemotherapy-based neoadjuvant treatment (RR = 0.675, 95% CI = 0.463-0.985; P = 0.042).\n\nCONCLUSION\nThis meta-analysis indicated that p53 status may be a useful predictive biomarker for response to chemotherapy in gastric cancer. Further prospective studies with larger sample sizes and better study designs are required to confirm our findings.", "authors": [ "Xu, HY", "Xu, WL", "Wang, LQ", "Chen, MB", "Shen, HL" ], "is_common_article": false, "date_published": 20140000, "date_completed": 20150601, "format": "Article", "pub_med_id": 24740294, "title": "Relationship between p53 status and response to chemotherapy in patients with gastric cancer: a meta-analysis.", "journal": "PloS one", "journal_abbreviation": "PLoS ONE", "journal_issue": "volume:9, issue:4" }, "24652989": { "abstract": "Mutations in TP53, NOTCH1, and SF3B1 were analyzed in the CLL8 study evaluating first-line therapy with fludarabine and cyclophosphamide (FC) or FC with rituximab (FCR) among patients with untreated chronic lymphocytic leukemia (CLL). TP53, NOTCH1, and SF3B1 were mutated in 11.5%, 10.0%, and 18.4% of patients, respectively. NOTCH1(mut) and SF3B1(mut) virtually showed mutual exclusivity (0.6% concurrence), but TP53(mut) was frequently found in NOTCH1(mut) (16.1%) and in SF3B1(mut) (14.0%) patients. There were few significant associations with clinical and laboratory characteristics, but genetic markers had a strong influence on response and survival. In multivariable analyses, an independent prognostic impact was found for FCR, thymidine kinase (TK) ≥10 U/L, unmutated IGHV, 11q deletion, 17p deletion, TP53(mut), and SF3B1(mut) on progression-free survival; and for FCR, age ≥65 years, Eastern Cooperative Oncology Group performance status ≥1, β2-microglobulin ≥3.5 mg/L, TK ≥10 U/L, unmutated IGHV, 17p deletion, and TP53(mut) on overall survival. Notably, predictive marker analysis identified an interaction of NOTCH1 mutational status and treatment in that rituximab failed to improve response and survival in patients with NOTCH1(mut). In conclusion, TP53 and SF3B1 mutations appear among the strongest prognostic markers in CLL patients receiving current-standard first-line therapy. NOTCH1(mut) was identified as a predictive marker for decreased benefit from the addition of rituximab to FC. This study is registered at www.clinicaltrials.gov as #NCT00281918.", "authors": [ "Stilgenbauer, S", "Schnaiter, A", "Paschka, P", "Zenz, T", "Rossi, M", "Döhner, K", "Bühler, A", "Böttcher, S", "Ritgen, M", "Kneba, M", "Winkler, D", "Tausch, E", "Hoth, P", "Edelmann, J", "Mertens, D", "Bullinger, L", "Bergmann, M", "Kless, S", "Mack, S", "Jäger, U", "Patten, N", "Wu, L", "Wenger, MK", "Fingerle-Rowson, G", "Lichter, P", "Cazzola, M", "Wendtner, CM", "Fink, AM", "Fischer, K", "Busch, R", "Hallek, M", "Döhner, H" ], "is_common_article": false, "date_published": 20140522, "date_completed": 20140902, "format": "Article", "pub_med_id": 24652989, "title": "Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial.", "journal": "Blood", "journal_abbreviation": "Blood", "journal_issue": "volume:123, issue:21" }, "24619868": { "abstract": "B lymphoblastic leukemia/lymphoma (ALL) are subdivided by the WHO classification into five subgroups defined by specific translocations and two further subgroups defined by the number of chromosomes. The hypodiploid subgroup is heterogeneous and comprises ALL with a chromosome number of <46. To characterize a specific subset with low hypodiploid karyotype, we performed chromosome banding analysis, FISH, array comparative genomic hybridization, and mutational analyses of FBXW7, NOTCH1, KRAS, NRAS, TP53, and IKZF1 in 29 cases. We observed a nonrandom pattern of chromosome losses, including chromosomes 3, 7, 13, 15, 16, and 17. A deletion encompassing the CDKN2A/B locus was the only recurrent structural abnormality. A duplication of the low hypodiploid karyotype occurred frequently, resulting in a near triploid karyotype based on the definition by merely counting chromosomes but in fact was a very low tetraploid chromosome set. Mutational analyses revealed no mutations in IKZF1, FBXW7, NOTCH1, and KRAS and only one mutation in NRAS. However, we discovered a high frequency of TP53 mutations in 93% (27/29) of cases. In 26/27 cases with TP53 mutation, the second TP53 allele was lost due to monosomy 17. Median overall survival was short (18.5 months), which might be related to the high frequency of TP53 alterations. Therefore, ALL with low hypodiploidy is characterized by a typical pattern of chromosome losses and a remarkably high TP53 mutation frequency. Our data suggest the introduction of a novel WHO entity within the B lymphoblastic leukemia/lymphoma group showing low hypodiploid/very low tetraploid karyotype and concomitant TP53 mutation.", "authors": [ "Mühlbacher, V", "Zenger, M", "Schnittger, S", "Weissmann, S", "Kunze, F", "Kohlmann, A", "Bellos, F", "Kern, W", "Haferlach, T", "Haferlach, C" ], "is_common_article": false, "date_published": 20140600, "date_completed": 20141010, "format": "Article", "pub_med_id": 24619868, "title": "Acute lymphoblastic leukemia with low hypodiploid/near triploid karyotype is a specific clinical entity and exhibits a very high TP53 mutation frequency of 93%.", "journal": "Genes, chromosomes & cancer", "journal_abbreviation": "Genes Chromosomes Cancer", "journal_issue": "volume:53, issue:6" }, "23788249": { "abstract": "In clinical exome and genome sequencing, there is a potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing but of medical value for patient care. The American College of Medical Genetics and Genomics (ACMG) recently published a policy statement on clinical sequencing that emphasized the importance of alerting the patient to the possibility of such results in pretest patient discussions, clinical testing, and reporting of results. The ACMG appointed a Working Group on Incidental Findings in Clinical Exome and Genome Sequencing to make recommendations about responsible management of incidental findings when patients undergo exome or genome sequencing. This Working Group conducted a year-long consensus process, including an open forum at the 2012 Annual Meeting and review by outside experts, and produced recommendations that have been approved by the ACMG Board. Specific and detailed recommendations, and the background and rationale for these recommendations, are described herein. The ACMG recommends that laboratories performing clinical sequencing seek and report mutations of the specified classes or types in the genes listed here. This evaluation and reporting should be performed for all clinical germline (constitutional) exome and genome sequencing, including the \"normal\" of tumor-normal subtractive analyses in all subjects, irrespective of age but excluding fetal samples. We recognize that there are insufficient data on penetrance and clinical utility to fully support these recommendations, and we encourage the creation of an ongoing process for updating these recommendations at least annually as further data are collected.", "authors": [ "Green, RC", "Berg, JS", "Grody, WW", "Kalia, SS", "Korf, BR", "Martin, CL", "McGuire, AL", "Nussbaum, RL", "O'Daniel, JM", "Ormond, KE", "Rehm, HL", "Watson, MS", "Williams, MS", "Biesecker, LG" ], "is_common_article": false, "date_published": 20130700, "date_completed": 20140508, "format": "Article", "pub_med_id": 23788249, "title": "ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.", "journal": "Genetics in medicine : official journal of the American College of Medical Genetics", "journal_abbreviation": "Genet. Med.", "journal_issue": "volume:15, issue:7" }, "27288520": { "abstract": "The clinical and prognostic relevance of many recently identified driver gene mutations in adult acute myeloid leukemia (AML) is poorly defined. We sequenced the coding regions or hotspot areas of 68 recurrently mutated genes in a cohort of 664 patients aged 18 to 86 years treated on 2 phase 3 trials of the German AML Cooperative Group (AMLCG). The median number of 4 mutations per patient varied according to cytogenetic subgroup, age, and history of previous hematologic disorder or antineoplastic therapy. We found patterns of significantly comutated driver genes suggesting functional synergism. Conversely, we identified 8 virtually nonoverlapping patient subgroups, jointly comprising 78% of AML patients, that are defined by mutually exclusive genetic alterations. These subgroups, likely representing distinct underlying pathways of leukemogenesis, show widely divergent outcomes. Furthermore, we provide detailed information on associations between gene mutations, clinical patient characteristics, and therapeutic outcomes in this large cohort of uniformly treated AML patients. In multivariate analyses including a comprehensive set of molecular and clinical variables, we identified DNMT3A and RUNX1 mutations as important predictors of shorter overall survival (OS) in AML patients <60 years, and particularly in those with intermediate-risk cytogenetics. NPM1 mutations in the absence of FLT3-ITD, mutated TP53, and biallelic CEBPA mutations were identified as important molecular prognosticators of OS irrespective of patient age. In summary, our study provides a comprehensive overview of the spectrum, clinical associations, and prognostic relevance of recurrent driver gene mutations in a large cohort representing a broad spectrum and age range of intensively treated AML patients.", "authors": [ "Metzeler, KH", "Herold, T", "Rothenberg-Thurley, M", "Amler, S", "Sauerland, MC", "Görlich, D", "Schneider, S", "Konstandin, NP", "Dufour, A", "Bräundl, K", "Ksienzyk, B", "Zellmeier, E", "Hartmann, L", "Greif, PA", "Fiegl, M", "Subklewe, M", "Bohlander, SK", "Krug, U", "Faldum, A", "Berdel, WE", "Wörmann, B", "Büchner, T", "Hiddemann, W", "Braess, J", "Spiekermann, K" ], "is_common_article": false, "date_published": 20160804, "date_completed": 20170731, "format": "Article", "pub_med_id": 27288520, "title": "Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia.", "journal": "Blood", "journal_abbreviation": "Blood", "journal_issue": "volume:128, issue:5" }, "23759327": { "abstract": "CONTEXT\nProstate cancer (PCa) is a clinically heterogeneous disease with marked variability in patient outcomes. Molecular characterization has revealed striking mutational heterogeneity that may underlie the variable clinical course of the disease.\n\nOBJECTIVE\nIn this review, we discuss the common genomic alterations that form the molecular basis of PCa, their functional significance, and the potential to translate this knowledge into patient care.\n\nEVIDENCE ACQUISITION\nWe reviewed the relevant literature, with a particular focus on recent studies on somatic alterations in PCa.\n\nEVIDENCE SYNTHESIS\nAdvances in sequencing technology have resulted in an explosion of data regarding the mutational events underlying the development and progression of PCa. Heterogeneity is the norm; few abnormalities in specific genes are highly recurrent, but alterations in certain signaling pathways do predominate. These alterations include those in pathways known to affect tumorigenesis in a wide spectrum of tissues, such as the phosphoinositide 3-kinase/phosphatase and tensin homolog/Akt pathway, cell cycle regulation, and chromatin regulation. Alterations more specific to PCa are also observed, particularly gene fusions of ETS transcription factors and alterations in androgen signaling. Mounting data suggest that PCa can be subdivided based on a molecular profile of genetic alterations.\n\nCONCLUSIONS\nMajor advances have been made in cataloging the genomic alterations in PCa and understanding the molecular mechanisms underlying the disease. These findings raise the possibility that PCa could soon transition from being a poorly understood, heterogeneous disease with a variable clinical course to being a collection of homogenous subtypes identifiable by molecular criteria, associated with distinct risk profiles, and perhaps amenable to specific management strategies or targeted therapies.", "authors": [ "Barbieri, CE", "Bangma, CH", "Bjartell, A", "Catto, JW", "Culig, Z", "Grönberg, H", "Luo, J", "Visakorpi, T", "Rubin, MA" ], "is_common_article": false, "date_published": 20131000, "date_completed": 20140401, "format": "Article", "pub_med_id": 23759327, "title": "The mutational landscape of prostate cancer.", "journal": "European urology", "journal_abbreviation": "Eur. Urol.", "journal_issue": "volume:64, issue:4" }, "15977174": { "abstract": "The TP53 tumor suppressor gene is the most frequent target for genetic alterations in human cancer. TP53 gene alterations may result in the gain of oncogenic functions such as neoangiogenesis and resistance to therapy. The TP53 germ line mutation c.659A>C (p.Y220S) was identified in stored DNA from related patients with Li-Fraumeni syndrome (LFS) who died after developing clinically aggressive tumors. All of the patients were treated with protocols that included doxorubicin hydrochloride (DX) as a pivotal drug. To define the in vitro mutational phenotype of this germ line mutation, we used murine fibroblasts explanted from wild-type (wt) and p53 knockout (KO) mice from the same littermate. p53Y220S and p53R175H fibroblasts, obtained from p53KO fibroblasts transfected with expression vectors encoding the human Y220S and R175H p53 mutants, respectively, exhibited resistance to DX treatment. Moreover, p53Y220S fibroblasts exhibited angiogenetic properties, and after DX treatment, p53Y220S failed to translocate into the nucleus and showed an increase in its cytosolic levels. DX treatment does not influence p53 distribution within the nuclear and cytosolic compartments in p53R175H fibroblasts. Peroxiredoxin II (Prx II), a protein that is involved in eliminating reactive oxygen species (ROS), showed increased expression intensity in p53Y220S fibroblasts after DX treatment, as observed by two-dimensional electrophoresis analysis. Moreover, Thioredoxin (Trx), a protein that cooperates with Prx II, is overexpressed in p53Y220S mutants under basal conditions. These data suggest a relationship between the presence of the p53Y220S mutation and enhanced levels of Prx II and Trx in mutant fibroblasts. Since one of the mechanisms of the DX antitumor effect has been ascribed to production of ROS, future studies will evaluate the involvement of PrxII and Trx in the chemoresistance of p53Y220S fibroblasts to DX.", "authors": [ "Capponcelli, S", "Pedrini, E", "Cerone, MA", "Corti, V", "Fontanesi, S", "Alessio, M", "Bachi, A", "Soddu, S", "Ribatti, D", "Picci, P", "Helman, LJ", "Cantelli-Forti, G", "Sangiorgi, L" ], "is_common_article": false, "date_published": 20050800, "date_completed": 20060717, "format": "Article", "pub_med_id": 15977174, "title": "Evaluation of the molecular mechanisms involved in the gain of function of a Li-Fraumeni TP53 mutation.", "journal": "Human mutation", "journal_abbreviation": "Hum. Mutat.", "journal_issue": "volume:26, issue:2" }, "23894400": { "abstract": "Sarcomas are a key feature of Li-Fraumeni and related syndromes (LFS/LFL), associated with germline TP53 mutations. Current penetrance estimates for TP53 mutations are subject to significant ascertainment bias. The International Sarcoma Kindred Study is a clinic-based, prospective cohort of adult-onset sarcoma cases, without regard to family history. The entire cohort was screened for mutations in TP53 using high-resolution melting analysis and Sanger sequencing, and multiplex-ligation-dependent probe amplification and targeted massively parallel sequencing for copy number changes. Pathogenic TP53 mutations were detected in blood DNA of 20/559 sarcoma probands (3.6%); 17 were germline and 3 appeared to be somatically acquired. Of the germline carriers, one appeared to be mosaic, detectable in the tumor and blood, but not epithelial tissues. Germline mutation carriers were more likely to have multiple cancers (47% vs 15% for non-carriers, P = 3.0×10(-3)), and earlier cancer onset (33 vs 48 years, P = 1.19×10(-3)). The median survival of mutation carriers following first cancer diagnosis was not significantly different from non-carriers. Only 10/17 (59%) pedigrees met classical or Chompret criteria for LFS. In summary, germline TP53 mutations are not rare in adult patients with sarcoma, with implications for screening, surveillance, treatment and genetic counselling of carriers and family members.", "authors": [ "Mitchell, G", "Ballinger, ML", "Wong, S", "Hewitt, C", "James, P", "Young, MA", "Cipponi, A", "Pang, T", "Goode, DL", "Dobrovic, A", "Thomas, DM" ], "is_common_article": false, "date_published": 20130000, "date_completed": 20140224, "format": "Article", "pub_med_id": 23894400, "title": "High frequency of germline TP53 mutations in a prospective adult-onset sarcoma cohort.", "journal": "PloS one", "journal_abbreviation": "PLoS ONE", "journal_issue": "volume:8, issue:7" }, "18596741": { "authors": [ "Bowen, D", "Groves, MJ", "Burnett, AK", "Patel, Y", "Allen, C", "Green, C", "Gale, RE", "Hills, R", "Linch, DC" ], "is_common_article": false, "date_published": 20090100, "date_completed": 20090206, "format": "Article", "pub_med_id": 18596741, "title": "TP53 gene mutation is frequent in patients with acute myeloid leukemia and complex karyotype, and is associated with very poor prognosis.", "journal": "Leukemia", "journal_abbreviation": "Leukemia", "journal_issue": "volume:23, issue:1" }, "15922892": { "abstract": "AIM\nTo investigate the role of coding region mutation and promoter hypermethylation of TP53 in adrenocortical cancer formation.\n\nMETHODS\nTwenty sporadic adrenocortical cancers (ACCs) and five normal adrenal tissue samples were available for analysis. Coding region mutation of TP53 in 20 ACCs was examined by polymerase chain amplification using intronic primers for exons 2-11 and direct sequencing of the product. In 10 ACCs and five normal adrenal tissue specimens, methylation of the 16 CpG sites within the TP53 promoter was examined using bisulphite methylation sequencing.\n\nRESULTS\nCoding region mutation in TP53 was demonstrated in 5 of 20 ACCs. There were four mis-sense mutations and one frameshift mutation. Four of 5 patients with a TP53 mutation had metastases at diagnosis or detected soon thereafter and 3 of 4 died of disease within 12 months of surgical resection. No methylation was seen in the TP53 promoter in 10 ACC and the five normal adrenal tissues examined.\n\nCONCLUSION\nCoding region mutation in TP53 occurs in 25% of ACCs with a trend toward a poorer prognosis. Promoter methylation of TP53 is not present in ACC as a mechanism for tumour suppressor gene (TSG) inactivation and, therefore, other genes in the 17p13 region are implicated in adrenal carcinogenesis.", "authors": [ "Sidhu, S", "Martin, E", "Gicquel, C", "Melki, J", "Clark, SJ", "Campbell, P", "Magarey, CJ", "Schulte, KM", "Röher, HD", "Delbridge, L", "Robinson, BG" ], "is_common_article": false, "date_published": 20050600, "date_completed": 20050721, "format": "Article", "pub_med_id": 15922892, "title": "Mutation and methylation analysis of TP53 in adrenal carcinogenesis.", "journal": "European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology", "journal_abbreviation": "Eur J Surg Oncol", "journal_issue": "volume:31, issue:5" }, "15695383": { "abstract": "Li-Fraumeni syndrome (LFS) is a clinically and genetically heterogeneous inherited cancer syndrome. Most cases ( approximately 70%) identified and characterized to date are associated with dominantly inherited germ line mutations in the tumor suppressor gene TP53 (p53) in chromosome 17p13.1. In a subset of non-p53 patients with LFS, CHEK2 in chromosome 22q11 has been identified as another predisposing locus. Studying a series of non-p53 LFS kindred, we have shown that there is additional genetic heterogeneity in LFS kindred with inherited predisposition at loci other than p53 or CHEK2. Using a genome-wide scan for linkage with complementing parametric and nonparametric analysis methods, we identified linkage to a region of approximately 4 cM in chromosome 1q23, a genomic region not previously implicated in this disease. Identification ofa third predisposing gene and its underlying mutation(s) should provide insight into other genetic events that predispose to the genesis of the diverse tumor types associated with LFS and its variants.", "authors": [ "Bachinski, LL", "Olufemi, SE", "Zhou, X", "Wu, CC", "Yip, L", "Shete, S", "Lozano, G", "Amos, CI", "Strong, LC", "Krahe, R" ], "is_common_article": false, "date_published": 20050115, "date_completed": 20050302, "format": "Article", "pub_med_id": 15695383, "title": "Genetic mapping of a third Li-Fraumeni syndrome predisposition locus to human chromosome 1q23.", "journal": "Cancer research", "journal_abbreviation": "Cancer Res.", "journal_issue": "volume:65, issue:2" }, "15381368": { "abstract": "Li-Fraumeni Syndrome (LFS) is a rare cancer syndrome caused by mutations in the TP53 gene. A number of tumor-associated germline mutations have been described in individuals from various ethnic origins although, thus far, none in affected individuals of German descent. Our work aimed to detect germline mutations in the TP53 gene in five index cases of German and Swiss origin with cancers typical of Li-Fraumeni syndrome. We analyzed all ten coding exons of the TP53 gene by direct sequencing of PCR products. We identified five mutations of which three were found in families with a strong history of LFS in several generations while two likely came about de novo. The five mutations include two missense mutations in exon 4 (Gly105Cys) and exon 7 (Arg248Gln), one deletion of 11 base pairs encompassing the splice acceptor sequence of exon 6 (IVS5-11_-1 del), one nonsense mutation in exon 6 (Arg196Stop), and one duplication of 4 base pairs in exon 8 (1020_1023dupCTGC). The functional consequence of the IVS5-11_-1del mutation on splicing of pre-mRNA was investigated by an in vitro assay. Our study reports the first germline mutations in patients of German and Swiss origin with LFS-related tumors. The frequent identification of de novo germline mutations emphasizes the importance of mutational analyses of the TP53 gene particularly in young patients with malignancies typical for LFS, but without a positive family history of this tumor syndrome.", "authors": [ "Bendig, I", "Mohr, N", "Kramer, F", "Weber, BH" ], "is_common_article": false, "date_published": 20041001, "date_completed": 20041026, "format": "Article", "pub_med_id": 15381368, "title": "Identification of novel TP53 mutations in familial and sporadic cancer cases of German and Swiss origin.", "journal": "Cancer genetics and cytogenetics", "journal_abbreviation": "Cancer Genet. Cytogenet.", "journal_issue": "volume:154, issue:1" }, "14726385": { "abstract": "The presence of p53 mutation or deletion predicts for poor response to conventional therapy in chronic lymphocytic leukemia (CLL). We sought to determine whether the humanized anti-CD52 antibody alemtuzumab was effective in this patient group. Thirty-six patients with fludarabine-refractory CLL were treated with alemtuzumab, 15 (42%) of whom had p53 mutations or deletions. Clinical responses in patients with p53 mutations, deletions, or both were noted in 6 (40%) of 15 versus 4 (19%) of 21 of patients without. The median response duration for this subset of patients was 8 months (range, 3-17 months). These data suggest that alemtuzumab may be an effective therapy for patients with CLL with p53 mutations or deletions.", "authors": [ "Lozanski, G", "Heerema, NA", "Flinn, IW", "Smith, L", "Harbison, J", "Webb, J", "Moran, M", "Lucas, M", "Lin, T", "Hackbarth, ML", "Proffitt, JH", "Lucas, D", "Grever, MR", "Byrd, JC" ], "is_common_article": false, "date_published": 20040501, "date_completed": 20040617, "format": "Article", "pub_med_id": 14726385, "title": "Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions.", "journal": "Blood", "journal_abbreviation": "Blood", "journal_issue": "volume:103, issue:9" }, "14583457": { "abstract": "A database has been created to collect information on families carrying a germ-line mutation in the TP53 gene and on families affected with Li-Fraumeni syndromes [Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like syndrome (LFL)]. Data from the published literature have been included. The database is available online at http://www.iarc.fr/p53, as part of the IARC TP53 Database. The analysis of the 265 families/individuals that have been included thus far has revealed several new findings. In classical LFS families with a germ-line TP53 mutation (83 families), the mean age of onset of breast cancer was significantly lower than in LFS families (16 families) without a TP53 mutation (34.6 versus 42.5 years; P = 0.0035). In individuals with a TP53 mutation, a correlation between the genotype and phenotype was found. Brain tumors were associated with missense TP53 mutations located in the DNA-binding loop that contact the minor groove of DNA (P = 0.01), whereas adrenal gland carcinomas were associated with missense mutations located in the loops opposing the protein-DNA contact surface (P = 0.003). Finally, mutations likely to result in a null phenotype (absence of the protein or loss of function) were associated with earlier onset brain tumors (P = 0.004). These observations have clinical implications for genetic testing and tumor surveillance in LFS/LFL families.", "authors": [ "Olivier, M", "Goldgar, DE", "Sodha, N", "Ohgaki, H", "Kleihues, P", "Hainaut, P", "Eeles, RA" ], "is_common_article": false, "date_published": 20031015, "date_completed": 20031222, "format": "Article", "pub_med_id": 14583457, "title": "Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype.", "journal": "Cancer research", "journal_abbreviation": "Cancer Res.", "journal_issue": "volume:63, issue:20" }, "12085209": { "abstract": "This report describes an individual with a rare choroid plexus papilloma in adulthood (age 29) after earlier having an osteosarcoma (age 22). The results from this study, and others, suggest that it may be advisable to consider the possibility of a germline p53 mutation in adults presenting with choroid plexus tumours. In the current study automated DNA sequencing of genomic DNA detected a novel germline 7 base pair insertion in exon 5 of the p53 gene in this patient. The alteration in frame would produce amino acid substitutions beginning with alanine to glycine at position 161 and a stop codon at position 182 in the mutated protein. Surprisingly two assays of p53 function gave apparently wild-type results on peripheral blood lymphocytes from this individual. These results led us to carry out more detailed functional tests on the mutant protein. The mutant allele was expressed either at very low levels or not at all in phytohaemagglutinin stimulated lymphocytes. Further, the mutant protein was completely non-functional in terms of its ability to transactivate a series of p53-responsive genes (p21(WAF1), bax, PIG3), to transrepress a target gene and to inhibit colony growth in transfected Saos-2 cells. However, surprisingly, data from irradiated peripheral blood lymphocytes and transfected Saos-2 cells, suggested that this truncated, mutant protein retains significant ability to induce apoptosis.", "authors": [ "Rutherford, J", "Chu, CE", "Duddy, PM", "Charlton, RS", "Chumas, P", "Taylor, GR", "Lu, X", "Barnes, DM", "Camplejohn, RS" ], "is_common_article": false, "date_published": 20020520, "date_completed": 20020802, "format": "Article", "pub_med_id": 12085209, "title": "Investigations on a clinically and functionally unusual and novel germline p53 mutation.", "journal": "British journal of cancer", "journal_abbreviation": "Br. J. Cancer", "journal_issue": "volume:86, issue:10" }, "12524418": { "abstract": "During a search for causative genes in patients with concurrent multiple primary colon tumours, we found a novel case with a germline mutation of the p53 gene, from GCC (Ala) to GTC (Val) at codon 189. Of the six primary colon tumours that this patient had, one large advanced carcinoma exhibited a somatic p53 mutation and a somatic APC mutation, in addition to the germline p53 mutation. Two early carcinomas and three adenomas had somatic APC mutations but no somatic p53 mutation or loss of the p53 allele. K-ras-2 mutations were detected in an advanced carcinoma and an early carcinoma. The present results suggest that a patient with a certain type of germline p53 mutation is predisposed to concurrent multiple colon tumours. It is also suggested that in such a patient, a somatic APC mutation is involved in tumour formation and that an additional somatic p53 mutation contributes to tumour progression.", "authors": [ "Miyaki, M", "Iijima, T", "Ohue, M", "Kita, Y", "Hishima, T", "Kuroki, T", "Iwama, T", "Mori, T" ], "is_common_article": false, "date_published": 20030200, "date_completed": 20030303, "format": "Article", "pub_med_id": 12524418, "title": "A novel case with germline p53 gene mutation having concurrent multiple primary colon tumours.", "journal": "Gut", "journal_abbreviation": "Gut", "journal_issue": "volume:52, issue:2" }, "12619118": { "abstract": "There are now reports of nearly 250 independent germline TP53 (p53) mutations in over 100 publications. Such mutations are typically associated with Li-Fraumeni or Li-Fraumeni-like syndrome, although many have been identified in cohorts of patients with tumors considered to be typical of LFS. In general, the spectrum of mutations that has been detected in the germline reflects that found in tumors, although there are some notable exceptions in certain tumor types. Detailed knowledge of the pedigrees allows a comprehensive analysis of genotype-phenotype correlations and an understanding of the tumors that are associated with germline TP53 mutations. This review will discuss the spectrum of mutations and the methods for mutation detection, the tumors associated with inheritance of a germline mutation, and some of the ethical and clinical problems in patients with a germline TP53 mutation.", "authors": [ "Varley, JM" ], "is_common_article": false, "date_published": 20030300, "date_completed": 20030324, "format": "Article", "pub_med_id": 12619118, "title": "Germline TP53 mutations and Li-Fraumeni syndrome.", "journal": "Human mutation", "journal_abbreviation": "Hum. Mutat.", "journal_issue": "volume:21, issue:3" }, "21714678": { "abstract": "BACKGROUND\nEZSCAN(®) (Impeto Medical, Paris, France), a noninvasive device that assesses sweat gland dysfunction using reverse iontophoresis, also detects early dysglycemia. Given the interrelationships among dysglycemia, vasculopathy, and neuropathy, EZSCAN may detect kidney disease in diabetes (DKD).\n\nMETHODS\nAn EZSCAN score (0-100) was calculated using a proprietary algorithm based on the chronoamperometry analysis. We measured the score in 50 Chinese type 2 diabetes patients without DKD (urinary albumin-creatinine ratio [ACR] <2.5 mg/mmol in men or ACR <3.5 mg/mmol in women and estimated glomerular filtration rate [eGFR] >90 mL/min/1.73 m(2)) and 50 with DKD (ACR ≥25 mg/mmol and eGFR <60 mL/min/1.73 m(2)). We used spline analysis to determine the threshold value of the score in detecting DKD and its sensitivity and specificity.\n\nRESULTS\nEZSCAN scores were highly correlated with log values of eGFR (r=0.67, P<0.0001) and ACR (r=-0.66, P<0.0001). Using a cutoff value of 55, the score had 94% sensitivity, 78% specificity, and a likelihood ratio of 4.2 to detect DKD with a positive predictive value of 81% and a negative predictive value of 93%. On multivariable analysis, DKD was independently associated with EZSCAN score (β=-0.72, P=0.02), smoking status (1=never, 0=current/former) (β=-2.37, P=0.02), retinopathy (1=yes, 0=no) (β=3.019, P=0.01), triglycerides (β=2.56, P=0.013), and blood hemoglobin (β=-0.613, P=0.04). Patients without DKD but low EZSCAN score (n=10) had longer duration of disease (median [interquartile range], 13 [9-17] vs. 8 [4-16] years; P=0.017) and were more likely to have retinopathy (36.7% vs. 5.1%, P=0.02), lower eGFR (98 [95.00-103] vs. 106 [98.5-115], P=0.036), and treatment with renin-angiotensin system blockers (81.8% vs. 25.6%, P=0.002) than those with a normal score.\n\nCONCLUSION\nEZSCAN may detect high-risk subjects for DKD in Chinese populations.", "authors": [ "Ozaki, R", "Cheung, KK", "Wu, E", "Kong, A", "Yang, X", "Lau, E", "Brunswick, P", "Calvet, JH", "Deslypere, JP", "Chan, JC" ], "is_common_article": false, "date_published": 20110900, "date_completed": 20120119, "format": "Article", "pub_med_id": 21714678, "title": "A new tool to detect kidney disease in Chinese type 2 diabetes patients: comparison of EZSCAN with standard screening methods.", "journal": "Diabetes technology & therapeutics", "journal_abbreviation": "Diabetes Technol. Ther.", "journal_issue": "volume:13, issue:9" }, "12610779": { "abstract": "To characterize cancer risk in heterozygous p53 mutation carriers, we analyzed cancer incidence in 56 germline p53 mutation carriers and 3,201 noncarriers from 107 kindreds ascertained through patients with childhood soft-tissue sarcoma who were treated at the University of Texas M. D. Anderson Cancer Center. We systematically followed members in these kindreds for cancer incidence for >20 years and evaluated their p53 gene status. We found seven kindreds with germline p53 mutations that include both missense and truncation mutation types. Kaplan-Meier analysis showed similar cancer risks between 21 missense and 35 truncation p53 mutation carriers (log-rank chi(2)=0.04; P=.84). We found a significantly higher cancer risk in female carriers than in male carriers (log-rank chi(2)=12.1; P<.001), a difference not explained by an excess of sex-specific cancer. The calculated standardized incidence ratio (SIR) showed that mutation carriers had a risk for all types of cancer that was much higher than that for the general population (SIR = 41.1; 95% confidence interval [CI] 29.9-55.0) whereas noncarriers had a risk for all types of cancer that was similar to that in the general population (SIR = 0.9; 95% CI 0.8-1.0). The calculated SIRs showed a >100-fold higher risk of sarcoma, female breast cancer, and hematologic malignancies for the p53 mutation carriers and agreed with the findings of an earlier segregation analysis based on the same cohort. These results quantitatively illustrated the spectrum of cancer risk in germline p53 mutation carriers and will provide valuable reference for the evaluation and treatment of patients with cancer.", "authors": [ "Hwang, SJ", "Lozano, G", "Amos, CI", "Strong, LC" ], "is_common_article": false, "date_published": 20030400, "date_completed": 20030505, "format": "Article", "pub_med_id": 12610779, "title": "Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk.", "journal": "American journal of human genetics", "journal_abbreviation": "Am. J. Hum. Genet.", "journal_issue": "volume:72, issue:4" }, "23175693": { "abstract": "PURPOSE\nAdrenocortical carcinoma (ACC) is a hallmark cancer in families with Li Fraumeni syndrome (LFS) caused by mutations in the TP53 gene. The prevalence of germline TP53 mutations in children diagnosed with ACC ranges from 50-97%. Although existing criteria advocate for TP53 testing in all patients with ACC regardless of age at diagnosis, the overall prevalence of germline mutations in patients diagnosed with ACC has not been well studied.\n\nPATIENTS AND METHODS\nA total of 114 patients with confirmed ACC evaluated in the University of Michigan Endocrine Oncology Clinic were prospectively offered genetic counseling and TP53 genetic testing, regardless of age at diagnosis or family history. Ninety-four of the 114 patients met with a genetic counselor (82.5%), with 53 of 94 (56.4%) completing TP53 testing; 9.6% (nine of 94) declined testing. The remainder (32 of 94; 34%) expressed interest in testing but did not pursue it for various reasons.\n\nRESULTS\nFour of 53 patients in this prospective, unselected series were found to have a TP53 mutation (7.5%). The prevalence of mutations in those diagnosed over age 18 was 5.8% (three of 52). There were insufficient data to estimate the prevalence in those diagnosed under age 18. None of these patients met clinical diagnostic criteria for classic LFS. Three of the families met criteria for Li Fraumeni-like syndrome; one patient met no existing clinical criteria for LFS or Li Fraumeni-like syndrome. Three of the four patients with mutations were diagnosed with ACC after age 45.\n\nCONCLUSIONS\nGenetic counseling and germline testing for TP53 should be offered to all patients with ACC. Restriction on age at diagnosis or strength of the family history would fail to identify mutation carriers.", "authors": [ "Raymond, VM", "Else, T", "Everett, JN", "Long, JM", "Gruber, SB", "Hammer, GD" ], "is_common_article": false, "date_published": 20130100, "date_completed": 20130307, "format": "Article", "pub_med_id": 23175693, "title": "Prevalence of germline TP53 mutations in a prospective series of unselected patients with adrenocortical carcinoma.", "journal": "The Journal of clinical endocrinology and metabolism", "journal_abbreviation": "J. Clin. Endocrinol. Metab.", "journal_issue": "volume:98, issue:1" }, "11595686": { "abstract": "PURPOSE\nThe p53 tumor suppressor gene plays a central role in cell cycle regulation and induction of apoptosis. We analyzed p53 alterations and their impact on response to chemotherapy and clinical outcome in ovarian cancer patients.\n\nEXPERIMENTAL DESIGN\nOne hundred seventy-eight ovarian carcinomas, snap frozen and stored at -80 degrees C, were analyzed for mutations of the p53 gene (exons 2-11) by single-strand conformation polymorphism and DNA sequencing and for p53 overexpression by immunohistochemistry (monoclonal antibody DO7).\n\nRESULTS\np53 mutations were found in 56% (99 of 178) of the tumors, and 62% of these were located in evolutionary highly conserved domains of the gene. Time to progression and overall survival were significantly shortened in patients with p53 mutations compared with wild-type p53 (P = 0.029 and P = 0.014) and patients with mutations in highly conserved domains as opposed to nonconserved domains or wild-type p53 (P = 0.010 and P = 0.007). p53 protein overexpression (>10% positively stained nuclei) was found in 62% (110 of 178). Time to progression and overall survival were shorter in cases with p53 overexpression (cutpoint, 10%: P = 0.071 and P = 0.056) but only marginally significant. Resistance to adjuvant cisplatin or carboplatin chemotherapy was significantly more frequent in patients with p53 overexpression (P = 0.001) or p53 missense mutations (P = 0.008) than patients with normal p53.\n\nCONCLUSIONS\np53 alterations correlate significantly with resistance to platinum-based chemotherapy, early relapse, and shortened overall survival in ovarian cancer patients in univariate analysis. In multivariable analysis though, p53 was not an independent prognostic factor.", "authors": [ "Reles, A", "Wen, WH", "Schmider, A", "Gee, C", "Runnebaum, IB", "Kilian, U", "Jones, LA", "El-Naggar, A", "Minguillon, C", "Schönborn, I", "Reich, O", "Kreienberg, R", "Lichtenegger, W", "Press, MF" ], "is_common_article": false, "date_published": 20011000, "date_completed": 20011205, "format": "Article", "pub_med_id": 11595686, "title": "Correlation of p53 mutations with resistance to platinum-based chemotherapy and shortened survival in ovarian cancer.", "journal": "Clinical cancer research : an official journal of the American Association for Cancer Research", "journal_abbreviation": "Clin. Cancer Res.", "journal_issue": "volume:7, issue:10" }, "22052707": { "abstract": "A total of 107 patients with chronic-phase primary myelofibrosis (PMF) were screened for TP53 mutations, which were detected in 4 (4%) cases: (i) E204E; GAG>GAA (silent exon 6); (ii) G245D; GGC>GAC (exon 7); (iii) R175H; CGC>CAC (exon 5); and (iv) six base insert (GGCGAG) after bp13767 (exon 6). Three (75%) of the four TP53-mutated cases also carried JAK2V617F whereas none were positive for MPL or IDH mutations. Two of the four TP53 mutated cases were also screened for TET2, ASXL1, DNMT3A, and EZH2 mutations and were negative. There was no significant difference in presenting features or survival between TP53 mutated and unmutated cases. TP53 exon 4 single nucleotide polymporphism (SNPs) data for codon 72 were available on 104 patients and included 56% with homozygous Arg72Arg, 33% with heterozygous Pro72Arg, and 11% with homozygous Pro72Pro. There were no significant differences among the three codon 72 genotypes in terms of presenting characteristics or survival.", "authors": [ "Raza, S", "Viswanatha, D", "Frederick, L", "Lasho, T", "Finke, C", "Knudson, R", "Ketterling, R", "Pardanani, A", "Tefferi, A" ], "is_common_article": false, "date_published": 20120200, "date_completed": 20130603, "format": "Article", "pub_med_id": 22052707, "title": "TP53 mutations and polymorphisms in primary myelofibrosis.", "journal": "American journal of hematology", "journal_abbreviation": "Am. J. Hematol.", "journal_issue": "volume:87, issue:2" }, "11498785": { "abstract": "The spectrum and frequency of cancers associated with germline TP53 mutations are uncertain. To address this issue a cohort of individuals from 28 families with Li-Fraumeni syndrome, segregating germline TP53 mutations was established. Predicted cancers were estimated by applying age, morphology, site and sex-specific UK cancer statistics to person-years at risk. Observed and predicted cancers were compared and two-sided P-values calculated. Cancer types occurring to excess and showing P-values <0.02, were designated strongly associated with germline TP53 mutations. These were removed from the data and a second round of analyses performed. Cancer types with P-values <0.02 and 0.02-0.05 in the second round analyses were considered moderately and weakly associated respectively. Strongly associated cancers were: breast carcinoma, soft tissue sarcomas, osteosarcoma, brain tumours, adrenocortical carcinoma, Wilms' tumour and phyllodes tumour. Carcinoma of pancreas was moderately associated. Leukaemia and neuroblastoma were weakly associated. Other common carcinomas including lung, colon, bladder, prostate, cervix and ovary did not occur to excess. Although breast carcinoma and sarcomas were numerically most frequent, the greatest increases relative to general population rates were in adrenocortical carcinoma and phyllodes tumour. We conclude that germline TP53 mutations do not simply increase general cancer risk. There are tissue-specific effects.", "authors": [ "Birch, JM", "Alston, RD", "McNally, RJ", "Evans, DG", "Kelsey, AM", "Harris, M", "Eden, OB", "Varley, JM" ], "is_common_article": false, "date_published": 20010802, "date_completed": 20010823, "format": "Article", "pub_med_id": 11498785, "title": "Relative frequency and morphology of cancers in carriers of germline TP53 mutations.", "journal": "Oncogene", "journal_abbreviation": "Oncogene", "journal_issue": "volume:20, issue:34" }, "11600572": { "abstract": "Mutations of the p53 tumor suppressor gene are the single most common genetic alterations in human cancers. Recently, a distinct nucleotide substitution was identified in exon 10 of the p53 gene, leading to an Arg337His mutation in 97% of children with adrenocortical tumors from Southern Brazil. In the present study, we investigated the presence of this mutation in a larger series of 55 patients (37 adults and 18 children) with benign and malignant sporadic adrenocortical tumors. None of the patients had family cancer histories that conformed to the criteria for Li-Fraumeni syndrome. Twenty-one asymptomatic close relatives of patients with p53 mutations and 60 normal unrelated individuals were also studied. The missense Arg337His mutation was identified in 19 patients (14 children and 5 adults), and 8 of 11 cases studied had LOH. Among the 19 patients with the Arg337His mutation, only one boy and three adults showed fatal evolution or recurrent metastases. This mutation was also identified in heterozygous state in asymptomatic first-degree relatives of the patients, indicating that Arg337His mutation was inherited in most cases. In contrast, this mutation was not found in 120 alleles of normal unrelated controls. In conclusion, the germ line Arg337His mutation of p53 protein is present at a high frequency (77.7%) in children with benign or malignant sporadic adrenocortical tumors, but it is not restricted to the pediatric group, since 13.5% of adults with adrenocortical tumors also had this mutation. The presence of this mutation was related to unfavorable prognosis in most of the adults, but not in the children with adrenocortical tumors.", "authors": [ "Latronico, AC", "Pinto, EM", "Domenice, S", "Fragoso, MC", "Martin, RM", "Zerbini, MC", "Lucon, AM", "Mendonca, BB" ], "is_common_article": false, "date_published": 20011000, "date_completed": 20011101, "format": "Article", "pub_med_id": 11600572, "title": "An inherited mutation outside the highly conserved DNA-binding domain of the p53 tumor suppressor protein in children and adults with sporadic adrenocortical tumors.", "journal": "The Journal of clinical endocrinology and metabolism", "journal_abbreviation": "J. Clin. Endocrinol. Metab.", "journal_issue": "volume:86, issue:10" }, "12509970": { "abstract": "In this study, we focused on p53 mutations in specific regions, including DNA-binding surface regions, to clarify the correlation between mutations within the specific regions of p53 and clinical outcomes of patients with oral cancers. We analyzed p53 mutations in 121 fresh primary oral squamous cell carcinomas (SCCs) by polymerase chain reaction-single-strand conformation polymorphism or a yeast functional assay. p53 mutations were detected in 51/121 (42%) cases. Mutation of p53 was not associated with any clinicopathological parameters; however, tumors containing specific p53 mutations, e.g. DNA-binding surface regions (L2, L3 and the LSH motif) and conserved regions (II-V), had significantly poorer prognoses than tumors with mutations outside of those regions. Moreover, locoregional failure, lymph node metastasis and the occurrence of subsequent distant metastasis were also significantly associated with mutations within DNA-binding surface regions. These data indicate that specific mutations of p53 could be important prognostic factors in oral SCCs.", "authors": [ "Yamazaki, Y", "Chiba, I", "Hirai, A", "Sugiura, C", "Notani, K", "Kashiwazaki, H", "Tei, K", "Totsuka, Y", "Fukuda, H" ], "is_common_article": false, "date_published": 20030200, "date_completed": 20030506, "format": "Article", "pub_med_id": 12509970, "title": "Specific p53 mutations predict poor prognosis in oral squamous cell carcinoma.", "journal": "Oral oncology", "journal_abbreviation": "Oral Oncol.", "journal_issue": "volume:39, issue:2" }, "11481490": { "abstract": "The incidence of pediatric adrenal cortical carcinoma (ACC) in southern Brazil is 10-15 times higher than that of pediatric ACC worldwide. Because childhood ACC is associated with Li-Fraumeni syndrome, we examined the cancer history and p53 status of 36 Brazilian patients and their families. Remarkably, 35 of 36 patients had an identical germ-line point mutation of p53 encoding an R337H amino acid substitution. Differences within intragenic polymorphic markers demonstrated that at least some mutant alleles arose independently, thus eliminating a founder effect. In tumor cells, the wild-type allele was deleted, and mutant p53 protein accumulated within the nuclei. Although these features are consistent with Li-Fraumeni syndrome-associated adrenal tumors, there was no history of increased cancer incidence among family members. Therefore, this inherited R337H p53 mutation represents a low-penetrance p53 allele that contributes in a tissue-specific manner to the development of pediatric ACC.", "authors": [ "Ribeiro, RC", "Sandrini, F", "Figueiredo, B", "Zambetti, GP", "Michalkiewicz, E", "Lafferty, AR", "DeLacerda, L", "Rabin, M", "Cadwell, C", "Sampaio, G", "Cat, I", "Stratakis, CA", "Sandrini, R" ], "is_common_article": false, "date_published": 20010731, "date_completed": 20010830, "format": "Article", "pub_med_id": 11481490, "title": "An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma.", "journal": "Proceedings of the National Academy of Sciences of the United States of America", "journal_abbreviation": "Proc. Natl. Acad. Sci. U.S.A.", "journal_issue": "volume:98, issue:16" }, "11332399": { "authors": [ "Chompret, A", "Abel, A", "Stoppa-Lyonnet, D", "Brugiéres, L", "Pagés, S", "Feunteun, J", "Bonaïti-Pellié, C" ], "is_common_article": false, "date_published": 20010100, "date_completed": 20010510, "format": "Article", "pub_med_id": 11332399, "title": "Sensitivity and predictive value of criteria for p53 germline mutation screening.", "journal": "Journal of medical genetics", "journal_abbreviation": "J. Med. Genet.", "journal_issue": "volume:38, issue:1" }, "23515910": { "abstract": "BACKGROUND\nThe value of p53 status for predicting response to chemotherapy-based treatment in patients with esophageal cancer has been controversial. We conducted a meta-analysis to elucidate the correlation of p53 status with the response to chemotherapy-based treatment.\n\nMETHODS\nStudies were searched in PubMed, Embase, and Web of Science (up to September 2012). The p53 status and response to therapy were defined and standardized. Subgroup analyses based on the treatment and histopathology were performed to explore the usefulness of p53 status for predicting response to therapy in esophageal cancer. Sensitivity analyses were conducted by removing specific studies to assess the effects of study quality.\n\nRESULTS\nWe included 28 studies with 1497 cases in our meta-analysis. Wild-type form of p53 status (low expression of p53 protein and/or wild-type p53 gene) was associated with high response to chemotherapy-based treatment in esophageal cancer (total major response [MR]: risk ratio [RR] = 1.09, 95 % CI = 1.03-1.16, P = .003; pathological MR: RR = 1.15, 95 % CI = 1.06-1.25, P = .001; total complete response [CR]: RR = 1.08, 95 % CI = 1.00-1.17, P = .040). The similar correlation between the wild-type form p53 and response to therapy were also detected in subgroup analyses (total MR, pathological MR, and total CR in chemoradiotherapy subgroup; total MR in chemotherapy subgroup; total MR and pathological CR in esophageal squamous cell carcinoma [ESCC]). Additionally, patients with wild-type form p53 status had high pathological complete response rate to neoadjuvant chemoradiotherapy in ESCC.\n\nCONCLUSIONS\nThe current meta-analysis suggested that p53 status might be a predictive biomarker for response to chemotherapy-based treatment in esophageal cancer.", "authors": [ "Zhang, SS", "Huang, QY", "Yang, H", "Xie, X", "Luo, KJ", "Wen, J", "Cai, XL", "Yang, F", "Hu, Y", "Fu, JH" ], "is_common_article": false, "date_published": 20130700, "date_completed": 20131217, "format": "Article", "pub_med_id": 23515910, "title": "Correlation of p53 status with the response to chemotherapy-based treatment in esophageal cancer: a meta-analysis.", "journal": "Annals of surgical oncology", "journal_abbreviation": "Ann. Surg. Oncol.", "journal_issue": "volume:20, issue:7" }, "23690417": { "abstract": "PURPOSE\nSeveral prognostic scoring systems have been proposed for chronic myelomonocytic leukemia (CMML), a disease in which some gene mutations-including ASXL1-have been associated with poor prognosis in univariable analyses. We developed and validated a prognostic score for overall survival (OS) based on mutational status and standard clinical variables.\n\nPATIENTS AND METHODS\nWe genotyped ASXL1 and up to 18 other genes including epigenetic (TET2, EZH2, IDH1, IDH2, DNMT3A), splicing (SF3B1, SRSF2, ZRSF2, U2AF1), transcription (RUNX1, NPM1, TP53), and signaling (NRAS, KRAS, CBL, JAK2, FLT3) regulators in 312 patients with CMML. Genotypes and clinical variables were included in a multivariable Cox model of OS validated by bootstrapping. A scoring system was developed using regression coefficients from this model.\n\nRESULTS\nASXL1 mutations (P < .0001) and, to a lesser extent, SRSF2 (P = .03), CBL (P = .003), and IDH2 (P = .03) mutations predicted inferior OS in univariable analysis. The retained independent prognostic factors included ASXL1 mutations, age older than 65 years, WBC count greater than 15 ×10(9)/L, platelet count less than 100 ×10(9)/L, and anemia (hemoglobin < 10 g/dL in female patients, < 11g/dL in male patients). The resulting five-parameter prognostic score delineated three groups of patients with median OS not reached, 38.5 months, and 14.4 months, respectively (P < .0001), and was validated in an independent cohort of 165 patients (P < .0001).\n\nCONCLUSION\nA new prognostic score including ASXL1 status, age, hemoglobin, WBC, and platelet counts defines three groups of CMML patients with distinct outcomes. Based on concordance analysis, this score appears more discriminative than those based solely on clinical parameters.", "authors": [ "Itzykson, R", "Kosmider, O", "Renneville, A", "Gelsi-Boyer, V", "Meggendorfer, M", "Morabito, M", "Berthon, C", "Adès, L", "Fenaux, P", "Beyne-Rauzy, O", "Vey, N", "Braun, T", "Haferlach, T", "Dreyfus, F", "Cross, NC", "Preudhomme, C", "Bernard, OA", "Fontenay, M", "Vainchenker, W", "Schnittger, S", "Birnbaum, D", "Droin, N", "Solary, E" ], "is_common_article": false, "date_published": 20130701, "date_completed": 20130829, "format": "Article", "pub_med_id": 23690417, "title": "Prognostic score including gene mutations in chronic myelomonocytic leukemia.", "journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", "journal_abbreviation": "J. Clin. Oncol.", "journal_issue": "volume:31, issue:19" }, "11219776": { "abstract": "Germ-line p53 mutations are associated with dominantly inherited Li-Fraumeni syndrome (LFS), which features early-onset sarcomas of bone and soft tissues, carcinomas of the breast and adrenal cortex, brain tumors, and acute leukemias. However, carriers of germ-line p53 mutations may also be at increased risk of other cancers. To clarify the tumor spectrum associated with inherited p53 mutations, we examined cancer occurrences among our series of 45 families, plus 140 other affected cases and kindreds reported in the literature. The analyses included all cancers in patients with a germ-line p53 mutation and their first-degree relatives with nearly 50% likelihood of being a carrier. Data were abstracted on tumor types and ages at diagnosis in eligible family members, and duplicate reports were excluded. Among 738 evaluable cancers, 569 (77%) were the six tumor types (breast and adrenocortical carcinomas, sarcomas of the bone and soft tissues, brain tumors, and leukemias) associated with LFS. The remaining 169 (23%) cancers included diverse carcinomas of the lung and gastrointestinal tract, lymphomas, and other neoplasms that occurred at much earlier ages than expected in the general population. Unusually early ages at diagnosis are characteristic of hereditary cancers and suggest that carriers of germ-line p53 mutations are at increased risk of a wide range of neoplasms. Future studies addressing age-specific penetrance and site-specific cancer risks can increase the utility of LFS as a model for understanding the role of p53 alterations in carcinogenesis and for designing diagnostic and preventive interventions for the broad array of neoplasms in this syndrome.", "authors": [ "Nichols, KE", "Malkin, D", "Garber, JE", "Fraumeni, JF", "Li, FP" ], "is_common_article": false, "date_published": 20010200, "date_completed": 20010510, "format": "Article", "pub_med_id": 11219776, "title": "Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers.", "journal": "Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology", "journal_abbreviation": "Cancer Epidemiol. Biomarkers Prev.", "journal_issue": "volume:10, issue:2" }, "1679237": { "abstract": "We detected a germ-line mutation of the p53 gene in a patient with a malignant ependymoma of the posterior fossa. This mutation, which was found at codon 242, resulted in an amino acid substitution in a highly conserved site of exon 7 of the p53 gene; the same mutation was found in both the germ-line and the tumor tissue. This is the most common region of previously described somatic p53 mutations in tumor specimens and of the germ-line p53 mutations in patients with the Li-Fraumeni cancer syndrome. Evaluation of the patient's family revealed several direct maternal and paternal relatives who had died at a young age from different types of cancer. The association of a germ-line p53 mutation with an intracranial malignancy and a strong family history of cancer suggests that p53 gene mutations predispose a person to malignancy and, like retinoblastoma mutations, may be inherited.", "authors": [ "Metzger, AK", "Sheffield, VC", "Duyk, G", "Daneshvar, L", "Edwards, MS", "Cogen, PH" ], "is_common_article": false, "date_published": 19910901, "date_completed": 19911003, "format": "Article", "pub_med_id": 1679237, "title": "Identification of a germ-line mutation in the p53 gene in a patient with an intracranial ependymoma.", "journal": "Proceedings of the National Academy of Sciences of the United States of America", "journal_abbreviation": "Proc. Natl. Acad. Sci. U.S.A.", "journal_issue": "volume:88, issue:17" }, "1978757": { "abstract": "Familial cancer syndromes have helped to define the role of tumor suppressor genes in the development of cancer. The dominantly inherited Li-Fraumeni syndrome (LFS) is of particular interest because of the diversity of childhood and adult tumors that occur in affected individuals. The rarity and high mortality of LFS precluded formal linkage analysis. The alternative approach was to select the most plausible candidate gene. The tumor suppressor gene, p53, was studied because of previous indications that this gene is inactivated in the sporadic (nonfamilial) forms of most cancers that are associated with LFS. Germ line p53 mutations have been detected in all five LFS families analyzed. These mutations do not produce amounts of mutant p53 protein expected to exert a trans-dominant loss of function effect on wild-type p53 protein. The frequency of germ line p53 mutations can now be examined in additional families with LFS, and in other cancer patients and families with clinical features that might be attributed to the mutation.", "authors": [ "Malkin, D", "Li, FP", "Strong, LC", "Fraumeni, JF", "Nelson, CE", "Kim, DH", "Kassel, J", "Gryka, MA", "Bischoff, FZ", "Tainsky, MA" ], "is_common_article": false, "date_published": 19901130, "date_completed": 19910103, "format": "Article", "pub_med_id": 1978757, "title": "Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms.", "journal": "Science (New York, N.Y.)", "journal_abbreviation": "Science", "journal_issue": "volume:250, issue:4985" }, "1591732": { "abstract": "The constant denaturant gel electrophoresis technique was used to screen for TP53 germ line mutations in 237 women with breast carcinoma (167 unselected patients, 30 patients with at least one first-degree relative with breast cancer, and 40 women diagnosed with breast cancer before age 35). A germ line mutation at codon 181 was noted in one of the unselected patients and a codon 245 mutation in one of the early-onset patients. Both had a family history of breast cancer and other malignancies suggestive of Li-Fraumeni syndrome. The codon 245 mutation was also present in this patient's affected mother.", "authors": [ "Børresen, AL", "Andersen, TI", "Garber, J", "Barbier-Piraux, N", "Thorlacius, S", "Eyfjörd, J", "Ottestad, L", "Smith-Sørensen, B", "Hovig, E", "Malkin, D" ], "is_common_article": false, "date_published": 19920601, "date_completed": 19920630, "format": "Article", "pub_med_id": 1591732, "title": "Screening for germ line TP53 mutations in breast cancer patients.", "journal": "Cancer research", "journal_abbreviation": "Cancer Res.", "journal_issue": "volume:52, issue:11" }, "1565143": { "abstract": "BACKGROUND\nRecent studies have identified germline mutations of the p53 tumor-suppressor gene in families with the Li-Fraumeni syndrome, a rare inherited disorder characterized by a high risk of sarcomas of bone and soft tissue, breast cancer, and other tumors. In this report, we address the possibility that some sporadic sarcomas may be associated with new germline mutations of the p53 gene, which would not be manifested as familial cancer unless the patient survived to reproduce.\n\nMETHODS\nWe studied DNA from peripheral leukocytes of 196 patients with sarcoma and from 200 controls. Of the 196 patients with sarcoma, 15 were selected because they had had multiple primary cancers or had a family history of cancer. The entire coding sequence and splice junctions of the p53 gene were analyzed for mutations.\n\nRESULTS\nEight germline mutations were found, three in patients with no known family history of cancer and five in patients with an unusual personal or family history of cancer. Four mutations caused amino acid substitutions, and four caused stop codons. These mutations were not present in any of the 200 controls.\n\nCONCLUSIONS\nNew germline mutations of the p53 gene are rare among patients with \"sporadic\" sarcoma but may be common in patients with sarcoma whose background includes either multiple primary cancers or a family history of cancer. Diverse mutations of this gene were associated with an increased likelihood of cancer; hence, the entire gene should be considered a target for heritable mutation. It appears that the group of patients with cancer who carry germline mutations of the p53 gene is more diverse than is suggested by the clinical definition of the Li-Fraumeni syndrome. The identification of carriers could be of substantial clinical importance.", "authors": [ "Toguchida, J", "Yamaguchi, T", "Dayton, SH", "Beauchamp, RL", "Herrera, GE", "Ishizaki, K", "Yamamuro, T", "Meyers, PA", "Little, JB", "Sasaki, MS" ], "is_common_article": false, "date_published": 19920514, "date_completed": 19920520, "format": "Article", "pub_med_id": 1565143, "title": "Prevalence and spectrum of germline mutations of the p53 gene among patients with sarcoma.", "journal": "The New England journal of medicine", "journal_abbreviation": "N. Engl. J. Med.", "journal_issue": "volume:326, issue:20" }, "1565144": { "abstract": "BACKGROUND\nAcquired mutations in the p53 tumor-suppressor gene have been detected in several human cancers, including colon, breast, and lung cancer. Inherited mutations (transmitted through the germline) of this gene can underlie the Li-Fraumeni syndrome, a rare familial association of breast cancer in young women, childhood sarcomas, and other malignant neoplasms. We investigated the possibility that p53 mutations in the germline are associated with second primary cancers that arise in children and young adults who would not be considered as belonging to Li-Fraumeni families.\n\nMETHODS\nGenomic DNA was extracted from the blood leukocytes of 59 children and young adults with a second primary cancer. The polymerase chain reaction, in combination with denaturant-gel electrophoresis and sequencing, was used to identify p53 gene mutations.\n\nRESULTS\nMutations of p53 that changed the predicted amino acid sequence were identified in leukocyte DNA from 4 of the 59 patients (6.8 percent). In three cases, the mutations were identical to ones previously found in the p53 gene. The fourth mutation was the first germline mutation to be identified in exon 9, at codon 325. Analysis of leukocyte DNA from close relatives of three of the patients indicated that the mutations were inherited, but cancer had developed in only one parent at the start of the study.\n\nCONCLUSIONS\nThese findings identify an important subgroup of young patients with cancer who carry germline mutations in the p53 tumor-suppressor gene but whose family histories are not indicative of the Li-Fraumeni syndrome. The early detection of such mutations would be useful not only in treating these patients, but also in identifying family members who may be at high risk for the development of tumors.", "authors": [ "Malkin, D", "Jolly, KW", "Barbier, N", "Look, AT", "Friend, SH", "Gebhardt, MC", "Andersen, TI", "Børresen, AL", "Li, FP", "Garber, J" ], "is_common_article": false, "date_published": 19920514, "date_completed": 19920520, "format": "Article", "pub_med_id": 1565144, "title": "Germline mutations of the p53 tumor-suppressor gene in children and young adults with second malignant neoplasms.", "journal": "The New England journal of medicine", "journal_abbreviation": "N. Engl. J. Med.", "journal_issue": "volume:326, issue:20" }, "1349175": { "abstract": "Multifocal osteogenic sarcoma patients without familial histories of increased tumor predisposition were examined for mutations in the highly conserved regions of the p53 gene. p53 point mutations were found in tumor DNA from each of the four patients we examined. A germ-line p53 mutation was detected in one of these patients, and a further rearrangement of the residual wild-type allele was detected in tumor tissue. p53 germ-line mutations can contribute to the enhanced predisposition to tumor development manifest in patients with multifocal osteosarcoma.", "authors": [ "Iavarone, A", "Matthay, KK", "Steinkirchner, TM", "Israel, MA" ], "is_common_article": false, "date_published": 19920501, "date_completed": 19920528, "format": "Article", "pub_med_id": 1349175, "title": "Germ-line and somatic p53 gene mutations in multifocal osteogenic sarcoma.", "journal": "Proceedings of the National Academy of Sciences of the United States of America", "journal_abbreviation": "Proc. Natl. Acad. Sci. U.S.A.", "journal_issue": "volume:89, issue:9" }, "3409256": { "abstract": "A search of the Cancer Family Registry of the National Cancer Institute revealed 24 kindreds with the syndrome of sarcoma, breast carcinoma, and other neoplasms in young patients. Cancer developed in an autosomal dominant pattern in 151 blood relatives, 119 (79%) of whom were affected before 45 years of age. These young patients had a total of 50 bone and soft tissue sarcomas of diverse histological subtypes and 28 breast cancers. Additional features of the syndrome included an excess of brain tumors (14 cases), leukemia (9 cases), and adrenocortical carcinoma (4 cases) before age 45 years. These neoplasms also accounted for 73% of the multiple primary cancers occurring in 15 family members. Six of these patients had second cancers linked to radiotherapy. The diversity of tumor types in this syndrome suggests pathogenetic mechanisms which differ from hereditary cancers arising in single organs or tissues. The syndrome is presently diagnosed on clinical grounds; laboratory markers are needed to identify high-risk individuals and families and to provide insights into susceptibility mechanisms that may be shared by a wide variety of cancers.", "authors": [ "Li, FP", "Fraumeni, JF", "Mulvihill, JJ", "Blattner, WA", "Dreyfus, MG", "Tucker, MA", "Miller, RW" ], "is_common_article": false, "date_published": 19880915, "date_completed": 19881011, "format": "Article", "pub_med_id": 3409256, "title": "A cancer family syndrome in twenty-four kindreds.", "journal": "Cancer research", "journal_abbreviation": "Cancer Res.", "journal_issue": "volume:48, issue:18" }, "6016796": { "authors": [ "Fraumeni, JF", "Miller, RW" ], "is_common_article": false, "date_published": 19670100, "date_completed": 19670328, "format": "Article", "pub_med_id": 6016796, "title": "Adrenocortical neoplasms with hemihypertrophy, brain tumors, and other disorders.", "journal": "The Journal of pediatrics", "journal_abbreviation": "J. Pediatr.", "journal_issue": "volume:70, issue:1" }, "15741269": { "abstract": "The human p53 tumor suppressor gene is located at the short arm of chromosome 17. A germinative mutation (Arg337His) in the tetramerization domain of p53 has been frequently identified in Brazilian children with sporadic adrenocortical tumors. Loss of heterozygosity at this region was demonstrated in the majority of the cases. In the present study, we performed deletion mapping of chromosome 17 in 30 adrenocortical tumors from 29 Brazilian patients (15 children and 14 adults). One boy had bilateral adrenocortical tumor. Sixteen patients had the germinative Arg337His mutation. Loss of heterozygosity analysis using six polymorphic microsatellite markers disclosed loss of the entire chromosome 17 in 18 tumors (10 adenomas and eight carcinomas) from 17 patients. The Arg337His mutation was present in 13 of them. Chromosomal instability involving chromosomes 2, 9, and 11 was also found in 47, 47, and 70% of the 17 patients who exhibited chromosome 17 losses, respectively. The concomitant loss of chromosomes 2, 9, 11, and 17 was evidenced exclusively in malignant tumors. Therefore, chromosomal instability involving three or more chromosomes may contribute to define the malignant adrenocortical lesions. In conclusion, we demonstrated a high frequency of biallelic inactivation of p53 derived from two distinct events, the germinative Arg337His mutation and the acquired loss of the entire chromosome 17. In addition, the isolated loss of the entire chromosome 17 did not correlate with aggressive tumor behavior in these patients with adrenocortical tumors.", "authors": [ "Pinto, EM", "Billerbeck, AE", "Fragoso, MC", "Mendonca, BB", "Latronico, AC" ], "is_common_article": false, "date_published": 20050500, "date_completed": 20050609, "format": "Article", "pub_med_id": 15741269, "title": "Deletion mapping of chromosome 17 in benign and malignant adrenocortical tumors associated with the Arg337His mutation of the p53 tumor suppressor protein.", "journal": "The Journal of clinical endocrinology and metabolism", "journal_abbreviation": "J. Clin. Endocrinol. Metab.", "journal_issue": "volume:90, issue:5" }, "7887414": { "abstract": "Germ-line mutations of the tumor-suppressor gene p53 have been observed in some families with the Li-Fraumeni syndrome (LFS), a familial cancer syndrome in which affected relatives develop a diverse set of early-onset malignancies including breast carcinoma, sarcomas, and brain tumors. The analysis of the p53 gene in LFS families has been limited, in most studies to date, to the region between exon 5 and exon 9. In order to determine the frequency and distribution of germ-line p53 mutations in LFS, we sequenced the 10 coding exons of the p53 gene in lymphocytes and fibroblast cell lines derived from 15 families with the syndrome. Germ-line mutations were observed in eight families. Six mutations were missense mutations located between exons 5 and 8. One mutation was a nonsense mutation in exon 6, and one mutation was a splicing mutation in intron 4, generating aberrant shorter p53 RNA(s). In three families, a mutation of the p53 gene was observed in the fibroblast cell line derived from the proband. However, the mutation was not found in affected relatives in two families and in the blood from the one individual, indicating that the mutation probably occurred during cell culture in vitro. In four families, no mutation was observed. This study indicates that germ-line p53 mutations in LFS are mostly located between exons 5 and 8 and that approximately 50% of patients with LFS have no germ-line mutations in the coding region of the p53 gene.(ABSTRACT TRUNCATED AT 250 WORDS)", "authors": [ "Frebourg, T", "Barbier, N", "Yan, YX", "Garber, JE", "Dreyfus, M", "Fraumeni, J", "Li, FP", "Friend, SH" ], "is_common_article": false, "date_published": 19950300, "date_completed": 19950413, "format": "Article", "pub_med_id": 7887414, "title": "Germ-line p53 mutations in 15 families with Li-Fraumeni syndrome.", "journal": "American journal of human genetics", "journal_abbreviation": "Am. J. Hum. Genet.", "journal_issue": "volume:56, issue:3" }, "8118819": { "abstract": "The entire coding sequence of the p53 gene was analysed for the presence of mutations in 12 families conforming to a restricted definition of Li-Fraumeni syndrome (classic LFS) and nine families with features of LFS conforming to a broader definition. Mutations were detected in seven families. Six were point mutations with one each affecting codons 175, 180, and 220 and three affecting codon 248. The seventh was a deletion/insertion mutation in exon 4. Germline mutations in p53 were a feature of families which included children with rhabdomyosarcoma and/or adrenal cortical carcinoma. Germline p53 mutations were detected in six of the nine families with such tumors. An analysis of these 7 mutations, together with 34 published examples, showed that more than one-half were transitions at CpG dinucleotides, suggesting that the majority of germline p53 mutations may arise as a result of spontaneous events. The most common cancers occurring in the 41 families with germline p53 mutations, in common with classic LFS, were bone and soft tissue sarcoma, breast cancer, brain tumors, leukemia, and adrenocortical carcinoma, although less than one-half of the probands with germline p53 mutations came from classic LFS families. More than one-half of the cancers overall and nearly one-third of the breast cancers were diagnosed before 30 years of age. These observations have important implications for asymptomatic carriers of germline p53 mutations, and there is a need for international collaboration in the development of protocols for the management of such families.", "authors": [ "Birch, JM", "Hartley, AL", "Tricker, KJ", "Prosser, J", "Condie, A", "Kelsey, AM", "Harris, M", "Jones, PH", "Binchy, A", "Crowther, D" ], "is_common_article": false, "date_published": 19940301, "date_completed": 19940407, "format": "Article", "pub_med_id": 8118819, "title": "Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families.", "journal": "Cancer research", "journal_abbreviation": "Cancer Res.", "journal_issue": "volume:54, issue:5" }, "8241511": { "abstract": "We studied 53 patients with B-cell chronic lymphocytic leukemia (B-CLL) and found mutations of the p53 gene in 15%. Patients with p53 gene mutations were found to have an aggressive form of B-CLL disease characterized by advanced Rai stage, rapid lymphocyte doubling time (LDT), and resistance to chemotherapy. While 27 of 29 treated patients (93%) without p53 mutations achieved a partial remission, only one of seven treated patients (14%) with p53 mutations achieved a partial remission (P = .00009). Adjusting for prognostic factors (age, sex, race, and Rai stage), patients with p53 gene mutations had a 13-fold greater risk of death than patients without p53 mutations (P = .013). In addition to examining the clinical relevance of p53 gene mutations in B-CLL, we investigated the possible role of p53 gene regulation in the expression of the multidrug resistance genes MDR1 and MDR3. We quantitated MDR1 and MDR3 mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR). Expression of both the MDR1 and MDR3 genes was independent of p53 gene mutation or prior drug treatment, and did not predict for clinical response. Our findings indicate that p53 gene mutations in B-CLL are associated with a poor clinical outcome and may be a prognostic indicator for drug resistance.", "authors": [ "el Rouby, S", "Thomas, A", "Costin, D", "Rosenberg, CR", "Potmesil, M", "Silber, R", "Newcomb, EW" ], "is_common_article": false, "date_published": 19931201, "date_completed": 19940104, "format": "Article", "pub_med_id": 8241511, "title": "p53 gene mutation in B-cell chronic lymphocytic leukemia is associated with drug resistance and is independent of MDR1/MDR3 gene expression.", "journal": "Blood", "journal_abbreviation": "Blood", "journal_issue": "volume:82, issue:11" }, "8718514": { "abstract": "Since the majority of germline mutations in the TP53 gene seem to occur in LFS or LFL families, and these are rare, research is best conducted in a collaborative setting (Li and Fraumeni, in press). In a report from a meeting at Bethesda in 1993, the following areas were outlined for collaborative study: the correlation (if any) of phenotypes with specific mutation; age specific penetrance; cumulative cancer incidence; gender differences in tumour development in carriers; the effects of DNA damaging agents on individuals with a TP53 mutation; the frequency of TP53 germline mutations in cohorts of patients with rare childhood tumours (eg adrenocortical carcinoma); and the psychosocial aspects of predictive TP53 testing. In addition, if, as seems likely from recent data, X irradiation in these individuals induces DNA damage that is tolerated, urgent collaborative studies are needed to investigate new methods of screening, such as magnetic resonance imaging. Treatment modalities should be carefully chosen, and for this reason alone, predictive testing may be desirable in all LFS and LFL families. Individuals carrying TP53 mutations could be offered chemoprevention within trials in an effort to reduce their mortality from cancer.", "authors": [ "Eeles, RA" ], "is_common_article": false, "date_published": 19950000, "date_completed": 19961011, "format": "Article", "pub_med_id": 8718514, "title": "Germline mutations in the TP53 gene.", "journal": "Cancer surveys", "journal_abbreviation": "Cancer Surv.", "journal_issue": "volume:25" }, "17215851": { "authors": [ "Chng, WJ", "Price-Troska, T", "Gonzalez-Paz, N", "Van Wier, S", "Jacobus, S", "Blood, E", "Henderson, K", "Oken, M", "Van Ness, B", "Greipp, P", "Rajkumar, SV", "Fonseca, R" ], "is_common_article": false, "date_published": 20070300, "date_completed": 20070413, "format": "Article", "pub_med_id": 17215851, "title": "Clinical significance of TP53 mutation in myeloma.", "journal": "Leukemia", "journal_abbreviation": "Leukemia", "journal_issue": "volume:21, issue:3" }, "8901856": { "abstract": "BACKGROUND\nThe p53 gene (also known as TP53) may be the most common genetic target involved in the malignant transformation of human cells. Direct sequence analysis has demonstrated that alteration of this gene occurs in approximately 45% of head and neck squamous cell carcinomas. The consequences of p53 mutations in these cancers with respect to tumor behavior and patient survival have not been rigorously determined.\n\nPURPOSE\nWe evaluated the implications of p53 mutations in relation to the control of locoregional disease and overall survival following radiation therapy.\n\nMETHODS\nData from 110 consecutive patients with invasive disease who were treated with primary radiation therapy (given with curative intent) or with adjuvant radiation therapy (following complete surgical extirpation of gross disease) were included in the analysis. A 1.8-kilobase fragment of the p53 gene encompassing exons 5-9 was amplified from the DNA of stored (frozen) tumor specimens; the amplified DNA was cloned and sequenced by use of standard techniques. Overall survival and locoregional disease-free survival after the completion of radiation therapy were estimated by the Kaplan-Meier method; survival comparisons were made by use of the logrank test or proportional hazards regression models. Reported P values are two-sided.\n\nRESULTS\nFortyeight (44%) of the 110 tumors had cells bearing p53 mutations. The risk of locoregional recurrence following either primary or adjuvant radiation therapy was significantly greater (i.e., the time to recurrence was shorter) for patients whose tumors contained mutant p53 genes (univariate model hazard ratio [HR] for p53 mutation versus wild-type = 2.2; 95% confidence interval [CI] = 1.2-4.1; P = .02). The presence of regional lymph node metastases (presence versus absence, HR = 2.0; 95% CI = 1.0-4.2; P = .05) and treatment type (primary radiation therapy versus surgery plus adjuvant radiation therapy, HR = 2.3; 95% CI = 1.2-4.3; P = .01) were also associated with greater risks of locoregional failure. The presence of p53 mutations and lymph node metastases and treatment with primary, as opposed to adjuvant, radiation therapy remained significant risk factors in multivariate regression analysis. No relationship was demonstrated between p53 status and overall survival (mutant versus wild-type, HR = 1.1; 95% CI = 0.6-2.1; P = .66); however, a relationship was shown for tumor stage and overall survival (stages III and IV [more advanced] versus stages I and II [less advanced], HR = 3.3; 95% CI = 1.0-10.8; P = .05). Mutation of the p53 gene was not associated with patient age, sex, tumor stage, primary tumor site, regional lymph node status, degree of tumor cell differentiation, or treatment method.\n\nCONCLUSIONS\nMutation of the p53 gene is associated with an increased risk of locoregional failure in patients with invasive head and neck squamous cell carcinoma who are treated with radiation therapy.", "authors": [ "Koch, WM", "Brennan, JA", "Zahurak, M", "Goodman, SN", "Westra, WH", "Schwab, D", "Yoo, GH", "Lee, DJ", "Forastiere, AA", "Sidransky, D" ], "is_common_article": false, "date_published": 19961106, "date_completed": 19961204, "format": "Article", "pub_med_id": 8901856, "title": "p53 mutation and locoregional treatment failure in head and neck squamous cell carcinoma.", "journal": "Journal of the National Cancer Institute", "journal_abbreviation": "J. Natl. Cancer Inst.", "journal_issue": "volume:88, issue:21" }, "9242456": { "abstract": "We have previously reported on the analysis of TP53 coding mutations in 12 classic Li-Fraumeni syndrome (LFS) families plus 9 families that were Li-Fraumeni-like (LFL) families (J. M. Birch et al., Cancer Res., 54: 1298-1304, 1994). Mutations were found in 6 of 12 LFS families and in 1 of 9 LFL families. We have now extended these studies to include an additional nine LFS and nine LFL families, and TP53 mutations have been detected in eight of nine LFS families and in three of nine LFL families. Six of the new mutations described here are the same as those previously identified in other Li-Fraumeni families and are missense mutations at codons 245, 248, and 273 (in two families); a nonsense mutation at codon 209; and a mutation at the splice donor site in exon 4. The other five mutations are novel germ-line mutations and include missense mutations at codons 136 and 344, a 2-bp deletion within codon 191, a splice acceptor mutation in intron 3, and a 167-bp deletion of part of exon 1 and intron 1. In addition, we have detected a codon 175 mutation in a family previously reported as TP53 negative. To summarize all of the data from the families we have studied in this and our previous report (J. M. Birch et al., Cancer Res., 54: 1298-1304, 1994), mutations have been detected in 15 of 21 LFS families (71%) and in 4 of 18 LFL families (22%). These figures are somewhat higher than those previously reported by us and others for the frequency of TP53 mutations in LFS and LFL families. This could reflect our analysis of all 11 exons of TP53, including noncoding regions, as well as the use of direct sequencing rather than other less-sensitive mutation detection methods.", "authors": [ "Varley, JM", "McGown, G", "Thorncroft, M", "Santibanez-Koref, MF", "Kelsey, AM", "Tricker, KJ", "Evans, DG", "Birch, JM" ], "is_common_article": false, "date_published": 19970801, "date_completed": 19970911, "format": "Article", "pub_med_id": 9242456, "title": "Germ-line mutations of TP53 in Li-Fraumeni families: an extended study of 39 families.", "journal": "Cancer research", "journal_abbreviation": "Cancer Res.", "journal_issue": "volume:57, issue:15" }, "23334668": { "abstract": "The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole-genome and exome sequencing of 40 cases, identified two subtypes that differ in the severity of aneuploidy, transcriptional profiles and submicroscopic genetic alterations. Near-haploid ALL with 24-31 chromosomes harbor alterations targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (encoding AIOLOS; 13%). In contrast, low-hypodiploid ALL with 32-39 chromosomes are characterized by alterations in TP53 (91.2%) that are commonly present in nontumor cells, IKZF2 (encoding HELIOS; 53%) and RB1 (41%). Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.", "authors": [ "Holmfeldt, L", "Wei, L", "Diaz-Flores, E", "Walsh, M", "Zhang, J", "Ding, L", "Payne-Turner, D", "Churchman, M", "Andersson, A", "Chen, SC", "McCastlain, K", "Becksfort, J", "Ma, J", "Wu, G", "Patel, SN", "Heatley, SL", "Phillips, LA", "Song, G", "Easton, J", "Parker, M", "Chen, X", "Rusch, M", "Boggs, K", "Vadodaria, B", "Hedlund, E", "Drenberg, C", "Baker, S", "Pei, D", "Cheng, C", "Huether, R", "Lu, C", "Fulton, RS", "Fulton, LL", "Tabib, Y", "Dooling, DJ", "Ochoa, K", "Minden, M", "Lewis, ID", "To, LB", "Marlton, P", "Roberts, AW", "Raca, G", "Stock, W", "Neale, G", "Drexler, HG", "Dickins, RA", "Ellison, DW", "Shurtleff, SA", "Pui, CH", "Ribeiro, RC", "Devidas, M", "Carroll, AJ", "Heerema, NA", "Wood, B", "Borowitz, MJ", "Gastier-Foster, JM", "Raimondi, SC", "Mardis, ER", "Wilson, RK", "Downing, JR", "Hunger, SP", "Loh, ML", "Mullighan, CG" ], "is_common_article": false, "date_published": 20130300, "date_completed": 20130530, "format": "Article", "pub_med_id": 23334668, "title": "The genomic landscape of hypodiploid acute lymphoblastic leukemia.", "journal": "Nature genetics", "journal_abbreviation": "Nat. Genet.", "journal_issue": "volume:45, issue:3" }, "21519010": { "abstract": "PURPOSE\nTo determine the frequency of TP53 mutations and the level of p53 protein expression by immunohistochemistry (IHC) in low-risk myelodysplastic syndromes (MDS) with del(5q) and to assess their impact on disease progression.\n\nPATIENTS AND METHODS\nPre- and postprogression bone marrow (BM) samples from 55 consecutive patients with International Prognostic Scoring System low risk (n = 32) or intermediate-1 risk (n = 23) were studied by next-generation sequencing of TP53. IHC for p53 was performed on 148 sequential BM samples.\n\nRESULTS\nTP53 mutations with a median clone size of 11% (range, 1% to 54%) were detected in 10 patients (18%) already at an early phase of the disease. Mutations were equally common in low-risk and intermediate-1-risk patients and were associated with evolution to acute myeloid leukemia (5 of 10 v 7 of 45; P = .045). Nine of 10 patients carrying mutations showed more than 2% BM progenitors with strong p53 staining. The probability of a complete cytogenetic response to lenalidomide was lower in mutated patients (0 of 7 v 12 of 24; P = .024).\n\nCONCLUSION\nBy using sensitive deep-sequencing technology, we demonstrated that TP53 mutated populations may occur at an early disease stage in almost a fifth of low-risk MDS patients with del(5q). Importantly, mutations were present years before disease progression and were associated with an increased risk of leukemic evolution. TP53 mutations could not be predicted by common clinical features but were associated with p53 overexpression. Our findings indicate a previously unrecognized heterogeneity of the disease which may significantly affect clinical decision making.", "authors": [ "Jädersten, M", "Saft, L", "Smith, A", "Kulasekararaj, A", "Pomplun, S", "Göhring, G", "Hedlund, A", "Hast, R", "Schlegelberger, B", "Porwit, A", "Hellström-Lindberg, E", "Mufti, GJ" ], "is_common_article": false, "date_published": 20110520, "date_completed": 20110715, "format": "Article", "pub_med_id": 21519010, "title": "TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression.", "journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", "journal_abbreviation": "J. Clin. Oncol.", "journal_issue": "volume:29, issue:15" }, "10612830": { "abstract": "The p53 tumor suppressor gene has proven to be one of the genes most often mutated in human cancers. It involves mainly point mutations leading to amino acid substitutions in the central region of the protein which impairs normal functions. Analysis of the mutational events that target the p53 gene has revealed evidence for both exogenous and endogenous mutational mechanisms. For example, the p53 mutational spectrum reveals evidence for a direct causal effect of ultraviolet radiation in skin cancer, of aflatoxin B1 in liver cancer, and of tobacco smoke in lung cancer. This novel field, molecular epidemiology of human cancer risk, has added a new dimension to classical associative epidemiology by providing a direct link between human cancer and carcinogen exposure. For such analysis, we devised a generic software called UMD (Universal Mutation Database). It was developed as a generic software to create locus-specific databases (LSDBs) with the 4(th) Dimension(R) package from ACI. This software includes an optimized structure to assist and secure data entry and to allow the input of various clinical data.", "authors": [ "Soussi, T", "Dehouche, K", "Béroud, C" ], "is_common_article": false, "date_published": 20000000, "date_completed": 20000202, "format": "Article", "pub_med_id": 10612830, "title": "p53 website and analysis of p53 gene mutations in human cancer: forging a link between epidemiology and carcinogenesis.", "journal": "Human mutation", "journal_abbreviation": "Hum. Mutat.", "journal_issue": "volume:15, issue:1" }, "10786679": { "abstract": "TP53 has been implicated in regulation of the cell cycle, DNA repair, and apoptosis. We studied, in primary breast tumors through direct cDNA sequencing of exons 2-11, whether TP53 gene mutations can predict response in patients with advanced disease to either first-line tamoxifen therapy (202 patients, of whom 55% responded) or up-front (poly)chemotherapy (41 patients, of whom 46% responded). TP53 mutations were detected in 90 of 243 (37%) tumors, and one-fourth of these mutations resulted in a premature termination of the protein. The mutations were observed in 32% (65 of 202) of the primary tumors of tamoxifen-treated patients and in 61% (25 of 41) of the primary tumors of the chemotherapy patients. TP53 mutation was significantly associated with a poor response to tamoxifen [31% versus 66%; odds ratio (OR), 0.22; 95% confidence interval (CI), 0.12-0.42; P < 0.0001]. Patients with TP53 gene mutations in codons that directly contact DNA or with mutations in the zinc-binding domain loop L3 showed the lowest response to tamoxifen (18% and 15% response rates, respectively). TP53 mutations were related, although not significantly, to a poor response to up-front chemotherapy (36% versus 63%; OR, 0.34; 95% CI, 0.09-1.24). In multivariate analysis for response including the classical parameters age and menopausal status, disease-free interval, dominant site of relapse, and levels of estrogen receptor and progesterone receptor, TP53 mutation was a significant predictor of poor response in the tamoxifen-treated group (OR, 0.29; 95% CI, 0.13-0.63; P = 0.0014). TP53-mutated and estrogen receptor-negative (<10 fmol/mg protein) tumors appeared to be the most resistant phenotype. Interestingly, the response of patients with TP53 mutations to chemotherapy after tamoxifen was not worse than that of patients without these mutations (50% versus 42%; OR, 1.35, nonsignificant). The median progression-free survival after systemic treatment was shorter for patients with a TP53 mutation than for patients with wild-type TP53 (6.6 and 0.6 months less for tamoxifen and up-front chemotherapy, respectively). In conclusion, TP53 gene mutation of the primary tumor is helpful in predicting the response of patients with metastatic breast disease to tamoxifen therapy. The type of mutation and its biological function should be considered in the analyses of the predictive value of TP53.", "authors": [ "Berns, EM", "Foekens, JA", "Vossen, R", "Look, MP", "Devilee, P", "Henzen-Logmans, SC", "van Staveren, IL", "van Putten, WL", "Inganäs, M", "Meijer-van Gelder, ME", "Cornelisse, C", "Claassen, CJ", "Portengen, H", "Bakker, B", "Klijn, JG" ], "is_common_article": false, "date_published": 20000415, "date_completed": 20000511, "format": "Article", "pub_med_id": 10786679, "title": "Complete sequencing of TP53 predicts poor response to systemic therapy of advanced breast cancer.", "journal": "Cancer research", "journal_abbreviation": "Cancer Res.", "journal_issue": "volume:60, issue:8" }, "17671205": { "abstract": "Cellular senescence is emerging as an important in vivo anticancer response elicited by multiple stresses, including currently used chemotherapeutic drugs. Nutlin-3a is a recently discovered small-molecule antagonist of the p53-destabilizing protein murine double minute-2 (MDM2) that induces cell cycle arrest and apoptosis in cancer cells with functional p53. Here, we report that nutlin-3a induces cellular senescence in murine primary fibroblasts, oncogenically transformed fibroblasts, and fibrosarcoma cell lines. No evidence of drug-induced apoptosis was observed in any case. Nutlin-induced senescence was strictly dependent on the presence of functional p53 as revealed by the fact that cells lacking p53 were completely insensitive to the drug, whereas cells lacking the tumor suppressor alternative reading frame product of the CDKN2A locus underwent irreversible cell cycle arrest. Interestingly, irreversibility was achieved in neoplastic cells faster than in their corresponding parental primary cells, suggesting that nutlin-3a and oncogenic signaling cooperate in activating p53. Our current results suggest that senescence could be a major cellular outcome of cancer therapy by antagonists of the p53-MDM2 interaction, such as nutlin-3a.", "authors": [ "Efeyan, A", "Ortega-Molina, A", "Velasco-Miguel, S", "Herranz, D", "Vassilev, LT", "Serrano, M" ], "is_common_article": false, "date_published": 20070801, "date_completed": 20070911, "format": "Article", "pub_med_id": 17671205, "title": "Induction of p53-dependent senescence by the MDM2 antagonist nutlin-3a in mouse cells of fibroblast origin.", "journal": "Cancer research", "journal_abbreviation": "Cancer Res.", "journal_issue": "volume:67, issue:15" }, "18689542": { "abstract": "The exact prognostic role of TP53 mutations (without 17p deletion) and any impact of the deletion without TP53 mutation in CLL are unclear. We studied 126 well-characterized CLL patients by direct sequencing and DHPLC to detect TP53 mutations (exons 2-11). Most patients with 17p deletions also had TP53 mutations (81%). Mutations in the absence of 17p deletions were found in 4.5%. We found a shorter survival for patients with TP53 mutation (n = 18; P = .002), which was more pronounced when analyzed from the time point of mutation detection (6.8 vs 69 months, P < .001). The survival was equally poor for patients with deletion 17p plus TP53 mutation (7.6 months, n = 13), TP53 mutation only (5.5 months, n = 5), and 17p deletion only (5.4 months, n = 3). The prognostic impact of TP53 mutation (HR 3.71) was shown to be independent of stage, VH status, and 11q and 17p deletion in multivariate analysis. Serial samples showed evidence of clonal evolution and increasing clone size during chemotherapy, suggesting that there may be patients where this treatment is potentially harmful. TP53 mutations are associated with poor sur-vival once they occur in CLL. The de-monstration of clonal evolution under selective pressure supports the biologic significance of TP53 mutations in CLL.", "authors": [ "Zenz, T", "Kröber, A", "Scherer, K", "Häbe, S", "Bühler, A", "Benner, A", "Denzel, T", "Winkler, D", "Edelmann, J", "Schwänen, C", "Döhner, H", "Stilgenbauer, S" ], "is_common_article": false, "date_published": 20081015, "date_completed": 20081016, "format": "Article", "pub_med_id": 18689542, "title": "Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up.", "journal": "Blood", "journal_abbreviation": "Blood", "journal_issue": "volume:112, issue:8" }, "18762572": { "abstract": "Paediatric choroid plexus carcinomas (CPC) and adrenocortical carcinomas (ACC) are exceedingly rare tumours, each occurring at an annual rate of 0.3 cases per million children or less. Although both tumour types are associated with Li-Fraumeni syndrome (LFS), the penetrance of germline TP53 mutations in CPC remains to be established. We report here a young boy without a family history of cancer who presented with CPC and subsequently ACC. Genetic testing revealed a novel de novo germline TP53 mutation (E285V). Neither tumour underwent loss of heterozygosity. Consistent with this observation, functional analyses demonstrated that E285V acts as a dominant negative mutant that is defective in regulating target gene expression, growth suppression and apoptosis. These results further strengthen the association between germline TP53 mutations and childhood CPC, even when occurring in the absence of familial tumour susceptibility.", "authors": [ "Russell-Swetek, A", "West, AN", "Mintern, JE", "Jenkins, J", "Rodriguez-Galindo, C", "Ribeiro, R", "Zambetti, GP" ], "is_common_article": false, "date_published": 20080900, "date_completed": 20080924, "format": "Article", "pub_med_id": 18762572, "title": "Identification of a novel TP53 germline mutation E285V in a rare case of paediatric adrenocortical carcinoma and choroid plexus carcinoma.", "journal": "Journal of medical genetics", "journal_abbreviation": "J. Med. Genet.", "journal_issue": "volume:45, issue:9" }, "19171829": { "abstract": "BACKGROUND\nFunctional single nucleotide polymorphisms (SNP) in codon 72 of TP53 have been shown to be a risk factor, a prognostic marker, and related factor to age at onset in various cancers.\n\nMETHODS\nWe investigated blood samples from 254 patients with glioblastoma and 238 healthy controls.\n\nRESULTS\nTP53 codon 72 status was not correlated with prognosis and did not differ between glioblastoma and control populations. However, the Pro/Pro genotype was overrepresented in patients <45 years (20.6% vs 6.4% in patients with glioblastoma >45 years, p = 0.002, vs 5.9% in control group, p = 0.001). We then confirmed this result on an independent series of young patients with glioblastoma. Finally, the analysis of tumor DNA found the Pro allele associated with occurrence of TP53 somatic mutation.\n\nCONCLUSION\nOur data suggest that TP53 functional variation is particularly critical for oncogenesis of glioblastoma in young patients.", "authors": [ "El Hallani, S", "Ducray, F", "Idbaih, A", "Marie, Y", "Boisselier, B", "Colin, C", "Laigle-Donadey, F", "Rodéro, M", "Chinot, O", "Thillet, J", "Hoang-Xuan, K", "Delattre, JY", "Sanson, M" ], "is_common_article": false, "date_published": 20090127, "date_completed": 20090220, "format": "Article", "pub_med_id": 19171829, "title": "TP53 codon 72 polymorphism is associated with age at onset of glioblastoma.", "journal": "Neurology", "journal_abbreviation": "Neurology", "journal_issue": "volume:72, issue:4" }, "19556618": { "abstract": "BACKGROUND\nLi-Fraumeni syndrome is an autosomal dominant cancer predisposition syndrome caused by germline mutations in the TP53 gene. The frequency of germline de novo TP53 mutations is largely unknown; few unequivocal de novo mutations have been reported.\n\nMETHODS AND RESULTS\nOf 341 patients with early onset cancer sent for clinical testing to a national reference laboratory, 75 patients had TP53 germline mutations. Five (7%) de novo mutations were identified, as well as an additional 10 TP53 germline mutations likely to be de novo by family history. The frequency of de novo TP53 mutations in this patient sample is at least 7% and may be as high as 20%.\n\nCONCLUSIONS\nThe possibility that de novo germline TP53 mutations are relatively common has implications for testing and the identification of potential Li-Fraumeni syndrome in patients with little or no family history of cancer.", "authors": [ "Gonzalez, KD", "Buzin, CH", "Noltner, KA", "Gu, D", "Li, W", "Malkin, D", "Sommer, SS" ], "is_common_article": false, "date_published": 20091000, "date_completed": 20091215, "format": "Article", "pub_med_id": 19556618, "title": "High frequency of de novo mutations in Li-Fraumeni syndrome.", "journal": "Journal of medical genetics", "journal_abbreviation": "J. Med. Genet.", "journal_issue": "volume:46, issue:10" }, "19652052": { "authors": [ "Tinat, J", "Bougeard, G", "Baert-Desurmont, S", "Vasseur, S", "Martin, C", "Bouvignies, E", "Caron, O", "Bressac-de Paillerets, B", "Berthet, P", "Dugast, C", "Bonaïti-Pellié, C", "Stoppa-Lyonnet, D", "Frébourg, T" ], "is_common_article": false, "date_published": 20090910, "date_completed": 20090925, "format": "Article", "pub_med_id": 19652052, "title": "2009 version of the Chompret criteria for Li Fraumeni syndrome.", "journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", "journal_abbreviation": "J. Clin. Oncol.", "journal_issue": "volume:27, issue:26" }, "19941080": { "abstract": "BACKGROUND\nResponse to chemotherapy and anatomical spread are significant prognostic factors in patients with esophageal squamous cell carcinoma (ESCC) treated by chemotherapy then surgery. Predicting the response to chemotherapy would allow significant optimization of cancer treatment.\n\nMETHODS\nGenomic mutation and protein expression of p53 were investigated retrospectively by polymerase chain reaction (PCR) single-strand conformation polymorphism (SSCP) and immunohistochemistry (IHC) using biopsy specimens from 77 ESCC patients before chemotherapy with 5-fluorouracil, adriamycin, and cisplatin. p53 status was correlated with various clinicopathological factors. Thereafter, we performed a prospective study of 20 consecutive patients to test our prediction model.\n\nRESULTS\nThe retrospective study showed mutant p53 genotype and positive p53 IHC staining in 46.8 and 55.8% of patients, respectively, which was not associated with patient's clinicopathological findings including initial tumor stage. Objective response to chemotherapy was observed in 65.9% of patients with wild genotype, but in only 16.7% of patients with mutant genotype. Patients with mutations in p53 therefore showed significantly poorer prognosis than those without mutant p53. In contrast, p53 IHC staining did not correlate with response to chemotherapy, curative resection rate or prognosis. In the prospective study, p53 mutation was seen in 50% (10/20) of patients and was again consistently associated with poorer response to chemotherapy and poorer prognosis.\n\nCONCLUSIONS\np53 genotype of pretreatment biopsy is a potentially useful predictor of response to chemotherapy and prognosis in ESCC patients. This information might be valuable to clinicians in deciding on the optimal clinical strategy in patients with ESCC.", "authors": [ "Yamasaki, M", "Miyata, H", "Fujiwara, Y", "Takiguchi, S", "Nakajima, K", "Nishida, T", "Yasuda, T", "Matsuyama, J", "Mori, M", "Doki, Y" ], "is_common_article": false, "date_published": 20100200, "date_completed": 20100506, "format": "Article", "pub_med_id": 19941080, "title": "p53 genotype predicts response to chemotherapy in patients with squamous cell carcinoma of the esophagus.", "journal": "Annals of surgical oncology", "journal_abbreviation": "Ann. Surg. Oncol.", "journal_issue": "volume:17, issue:2" }, "20182602": { "abstract": "Somatic mutations in the TP53 gene are one of the most frequent alterations in human cancers, and germline mutations are the underlying cause of Li-Fraumeni syndrome, which predisposes to a wide spectrum of early-onset cancers. Most mutations are single-base substitutions distributed throughout the coding sequence. Their diverse types and positions may inform on the nature of mutagenic mechanisms involved in cancer etiology. TP53 mutations are also potential prognostic and predictive markers, as well as targets for pharmacological intervention. All mutations found in human cancers are compiled in the IARC TP53 Database (http://www-p53.iarc.fr/). A human TP53 knockin mouse model (Hupki mouse) provides an experimental model to study mutagenesis in the context of a human TP53 sequence. Here, we summarize current knowledge on TP53 gene variations observed in human cancers and populations, and current clinical applications derived from this knowledge.", "authors": [ "Olivier, M", "Hollstein, M", "Hainaut, P" ], "is_common_article": false, "date_published": 20100100, "date_completed": 20100929, "format": "Article", "pub_med_id": 20182602, "title": "TP53 mutations in human cancers: origins, consequences, and clinical use.", "journal": "Cold Spring Harbor perspectives in biology", "journal_abbreviation": "Cold Spring Harb Perspect Biol", "journal_issue": "volume:2, issue:1" }, "20301488": { "abstract": "CLINICAL CHARACTERISTICS\nLi-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with the development of the following classic tumors: soft tissue sarcoma, osteosarcoma, pre-menopausal breast cancer, brain tumors, adrenocortical carcinoma (ACC), and leukemias. In addition, a variety of other neoplasms may occur. LFS-related cancers often occur in childhood or young adulthood and survivors have an increased risk for multiple primary cancers. Age-specific cancer risks have been calculated.\n\nDIAGNOSIS/TESTING\nLFS is diagnosed in individuals meeting established clinical criteria or in those who have a germline pathogenic variant in TP53 regardless of family cancer history. At least 70% of individuals diagnosed clinically have an identifiable germline pathogenic variant in TP53, the only gene so far identified in which mutation is definitively associated with LFS.\n\nMANAGEMENT\nTreatment of manifestations: Routine oncologic management is recommended for malignancies in individuals with LFS, with the exception of breast cancer, in which mastectomy rather than lumpectomy is recommended in order to reduce the risks of a second primary breast tumor and avoid radiation therapy. Concerns about increased risk for radiation-induced second primary tumors has led to more cautious use of therapeutic radiation in general, but most experts recommend that treatment efficacy be prioritized above concerns about late effects after careful analysis of risks and benefits. Prevention of primary manifestations: Prophylactic mastectomy to reduce the risk for breast cancer is an option for women with a germline TP53 pathogenic variant. Recent recommendations for colonoscopy may be considered surveillance as well as primary prevention of colorectal cancer. Prevention of secondary complications: Avoidance of exposure to radiation therapy, when possible, to reduce the risk of secondary radiation-induced malignancies. Surveillance: There are no definitive prospective data on the optimal methods for and efficacy of tumor surveillance for children or adults with a germline TP53 pathogenic variant. Currently, it is recommended that: (1) children and adults undergo comprehensive annual physical examination; (2) children and adults be encouraged see a physician promptly for evaluation of lingering symptoms and illnesses; (3) women undergo breast cancer monitoring, with annual breast MRI and twice annual clinical breast examination beginning at age 20-25 years. The use of mammograms has been controversial because of radiation exposure and limited sensitivity. When included, annual mammograms should alternate with breast MRI, with one modality every six months; (4) adults consider routine screening for colorectal cancer with colonoscopy every 2-3 years beginning no later than age 25 years; (5) individuals consider organ-targeted surveillance based on the pattern of cancer observed in their family. Intensified surveillance with whole-body MRI protocols for adults and children who carry a germline TP53 pathogenic variant are being evaluated in investigational settings. Agents/circumstances to avoid: People with germline TP53 pathogenic variants should: (1) avoid known carcinogens including sun exposure, tobacco use, occupational exposures, and excessive alcohol use; and (2) minimize exposure to diagnostic and therapeutic radiation. Evaluation of relatives at risk: It is appropriate to offer genetic counseling and testing to all relatives who are at risk of having a familial TP53 pathogenic variant.\n\nGENETIC COUNSELING\nLFS is inherited in an autosomal dominant manner. The proportion of individuals with a de novo germline TP53 pathogenic variant is estimated to be between 7% and 20%. Offspring of an affected individual have a 50% chance of inheriting the deleterious allelic variant. Predisposition testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the heritable pathogenic variant in the family has been identified.", "authors": [ "Pagon, RA", "Adam, MP", "Ardinger, HH", "Wallace, SE", "Amemiya, A", "Bean, LJH", "Bird, TD", "Fong, CT", "Mefford, HC", "Smith, RJH", "Stephens, K" ], "is_common_article": false, "format": "Book", "date_published": 19930000, "pub_med_id": 20301488, "date_completed": 20160000, "publisher": "University of Washington, Seattle", "title": "GeneReviews(®)" }, "20697090": { "abstract": "PURPOSE\nThe precise prognostic impact of TP53 mutation and its incorporation into treatment algorithms in chronic lymphocytic leukemia (CLL) is unclear. We set out to define the impact of TP53 mutations in CLL.\n\nPATIENTS AND METHODS\nWe assessed TP53 mutations by denaturing high-performance liquid chromatography (exons 2 to 11) in a randomized prospective trial (n = 375) with a follow-up of 52.8 months (German CLL Study Group CLL4 trial; fludarabine [F] v F + cyclophosphamide [FC]).\n\nRESULTS\nWe found TP53 mutations in 8.5% of patients (28 of 328 patients). None of the patients with TP53 mutation showed a complete response. In patients with TP53 mutation, compared with patients without TP53 mutation, median progression-free survival (PFS; 23.3 v 62.2 months, respectively) and overall survival (OS; 29.2 v 84.6 months, respectively) were significantly decreased (both P < .001). TP53 mutations in the absence of 17p deletions were found in 4.5% of patients. PFS and OS for patients with 17p deletion and patients with TP53 mutation in the absence of 17p deletion were similar. Multivariate analysis identified TP53 mutation as the strongest prognostic marker regarding PFS (hazard ratio [HR] = 3.8; P < .001) and OS (HR = 7.2; P < .001). Other independent predictors of OS were IGHV mutation status (HR = 1.9), 11q deletion (HR = 1.9), 17p deletion (HR = 2.3), and FC treatment arm (HR = 0.6).\n\nCONCLUSION\nCLL with TP53 mutation carries a poor prognosis regardless of the presence of 17p deletion when treated with F-based chemotherapy. Thus, TP53 mutation analysis should be incorporated into the evaluation of patients with CLL before treatment initiation. Patients with TP53 mutation should be considered for alternative treatment approaches.", "authors": [ "Zenz, T", "Eichhorst, B", "Busch, R", "Denzel, T", "Häbe, S", "Winkler, D", "Bühler, A", "Edelmann, J", "Bergmann, M", "Hopfinger, G", "Hensel, M", "Hallek, M", "Döhner, H", "Stilgenbauer, S" ], "is_common_article": false, "date_published": 20101010, "date_completed": 20101029, "format": "Article", "pub_med_id": 20697090, "title": "TP53 mutation and survival in chronic lymphocytic leukemia.", "journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", "journal_abbreviation": "J. Clin. Oncol.", "journal_issue": "volume:28, issue:29" }, "21056402": { "abstract": "DNA copy-number variations (CNVs) underlie many neuropsychiatric conditions, but they have been less studied in cancer. We report the association of a 17p13.1 CNV, childhood-onset developmental delay (DD), and cancer. Through a screen of over 4000 patients with diverse diagnoses, we identified eight probands harboring microdeletions at TP53 (17p13.1). We used a purpose-built high-resolution array with 93.75% breakpoint accuracy to fine map these microdeletions. Four patients were found to have a common phenotype including DD, hypotonia, and hand and foot abnormalities, constituting a unique syndrome. Notably, these patients were not affected with cancer. Moreover, none of the TP53-deletion patients affected with cancer (n = 4) had neurocognitive impairments. DD patients have larger deletions, which encompass but do not disrupt TP53, whereas cancer-affected patients harbor CNVs with at least one breakpoint within TP53. Most 17p13.1 deletions arise by Alu-mediated nonallelic homologous recombination. Furthermore, we identify a critical genomic region associated with DD and containing six underexpressed genes. We conclude that, although they overlap, 17p13.1 CNVs are associated with distinct phenotypes depending on the position of the breakpoint with respect to TP53. Further, detailed characterization of breakpoints revealed a common formation signature. Future studies should consider whether other loci in the genome also give rise to phenotypically distinct disorders by means of a common mechanism, resulting in a similar formation signature.", "authors": [ "Shlien, A", "Baskin, B", "Achatz, MI", "Stavropoulos, DJ", "Nichols, KE", "Hudgins, L", "Morel, CF", "Adam, MP", "Zhukova, N", "Rotin, L", "Novokmet, A", "Druker, H", "Shago, M", "Ray, PN", "Hainaut, P", "Malkin, D" ], "is_common_article": false, "date_published": 20101112, "date_completed": 20110124, "format": "Article", "pub_med_id": 21056402, "title": "A common molecular mechanism underlies two phenotypically distinct 17p13.1 microdeletion syndromes.", "journal": "American journal of human genetics", "journal_abbreviation": "Am. J. Hum. Genet.", "journal_issue": "volume:87, issue:5" }, "21467160": { "abstract": "PURPOSE\nTP53 is a key gene in cellular homeostasis and is frequently mutated in head and neck squamous cell carcinoma (HNSCC). There is a variety of TP53 mutations, each with its own biological and clinical implication. Aim of the study was to assess the prognostic significance of TP53 mutations in HNSCCs and to identify the most relevant mutation.\n\nEXPERIMENTAL DESIGN\nTP53 mutation status was investigated in 141 consecutive HNSCCs treated by surgery with radiotherapy when indicated and with a known human papilloma virus status. The type of mutation was correlated with overall and progression-free survival in a multivariate two-sided Cox regression analysis with wild type as reference.\n\nRESULTS\nA TP53 mutation was found in 88 (62.4%) of the carcinomas and was not significantly associated with overall survival (HR = 1.65, P = 0.11). Patients with a mutation resulting in a truncated protein (n = 36, 25.5%) had a significantly worse overall survival (HR = 2.54, P = 0.008) and progression-free survival (HR = 2.65, P = 0.002). Four of these mutations were at a splice site, 13 were nonsense mutations (produces stop codon), and 19 were insertions or deletions resulting in a frameshift. After multivariate analysis, a truncating mutation remained a significant prognosticator. A missense (i.e., nontruncating) mutation did not influence prognosis. Other ways of classification (disruptive vs. nondisruptive, hotspot vs. nonhotspot, and DNA binding vs. non-DNA binding) were less discriminative.\n\nCONCLUSION\nIn HNSCCs, a truncating TP53 mutation is associated with a poor prognosis. This patient group seems as a target population for adjuvant therapy with chemoradiation or viral vector-mediated TP53 gene transfer.", "authors": [ "Lindenbergh-van der Plas, M", "Brakenhoff, RH", "Kuik, DJ", "Buijze, M", "Bloemena, E", "Snijders, PJ", "Leemans, CR", "Braakhuis, BJ" ], "is_common_article": false, "date_published": 20110601, "date_completed": 20111227, "format": "Article", "pub_med_id": 21467160, "title": "Prognostic significance of truncating TP53 mutations in head and neck squamous cell carcinoma.", "journal": "Clinical cancer research : an official journal of the American Association for Cancer Research", "journal_abbreviation": "Clin. Cancer Res.", "journal_issue": "volume:17, issue:11" }, "21483000": { "abstract": "PURPOSE\nTP53 mutations have been described in chronic lymphocytic leukemia (CLL) and have been associated with poor prognosis in retrospective studies. We aimed to address the frequency and prognostic value of TP53 abnormalities in patients with CLL in the context of a prospective randomized trial.\n\nPATIENTS AND METHODS\nWe analyzed 529 CLL samples from the LRF CLL4 (Leukaemia Research Foundation Chronic Lymphocytic Leukemia 4) trial (chlorambucil v fludarabine with or without cyclophosphamide) at the time of random assignment for mutations in the TP53 gene. TP53 mutation status was correlated with response and survival data.\n\nRESULTS\nMutations of TP53 were found in 40 patients (7.6%), including 25 (76%) of 33 with 17p deletion and 13 (3%) of 487 without that deletion. There was no significant correlation between TP53 mutations and age, stage, IGHV gene mutations, CD38 and ZAP-70 expression, or any other chromosomal abnormality other than 17p deletion, in which concordance was high (96%). TP53 mutations were significantly associated with poorer overall response rates (27% v 83%; P < .001) and shorter progression-free survival (PFS) and overall survival (OS; 5-year PFS: 5% v 17%; 5-year OS: 20% v 59%; P < .001 for both). Multivariate analysis that included baseline clinical variables, treatment, and known adverse genetic factors confirmed that TP53 mutations have added prognostic value.\n\nCONCLUSION\nTP53 mutations are associated with impaired response and shorter survival in patients with CLL. Analysis of TP53 mutations should be performed in patients with CLL who have progressive disease before starting first-line treatment, and those with mutations should be selected for novel experimental therapies.", "authors": [ "Gonzalez, D", "Martinez, P", "Wade, R", "Hockley, S", "Oscier, D", "Matutes, E", "Dearden, CE", "Richards, SM", "Catovsky, D", "Morgan, GJ" ], "is_common_article": false, "date_published": 20110601, "date_completed": 20110728, "format": "Article", "pub_med_id": 21483000, "title": "Mutational status of the TP53 gene as a predictor of response and survival in patients with chronic lymphocytic leukemia: results from the LRF CLL4 trial.", "journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", "journal_abbreviation": "J. Clin. Oncol.", "journal_issue": "volume:29, issue:16" }, "21601526": { "abstract": "BACKGROUND\nIndividuals with Li-Fraumeni syndrome have a high lifetime risk of developing cancer. We assessed the feasibility and potential clinical effect of a comprehensive surveillance protocol in asymptomatic TP53 mutation carriers in families with this syndrome.\n\nMETHODS\nWe implemented a clinical surveillance protocol, using frequent biochemical and imaging studies, for asymptomatic TP53 mutation carriers on Jan 1, 2004, and did a prospective observational study of members of eight families with Li-Fraumeni syndrome who either chose to undergo surveillance or chose not to undergo surveillance. The primary outcome measure was detection of new cancers. The secondary outcome measure was overall survival.\n\nFINDINGS\nAs of Nov 1, 2010, 33 TP53 mutation carriers were identified, 18 of whom underwent surveillance. The surveillance protocol detected ten asymptomatic tumours in seven patients, including small, high-grade tumours and low-grade or premalignant tumours. All seven mutation carriers were alive after a median follow-up of 24 months (IQR 22-65 months). 12 high-grade, high-stage tumours developed in 10 individuals in the non-surveillance group, two of whom (20%) were alive at the end of follow-up (p=0·0417 for comparison with survival in the surveillance group). 3-year overall survival was 100% in the surveillance group and 21% (95% CI 4-48%) in the non-surveillance group (p=0·0155).\n\nINTERPRETATION\nOur findings show the feasibility of a clinical surveillance protocol for the detection of asymptomatic neoplasms in individuals with germline TP53 mutations. This strategy offers a management option for affected individuals, and its benefits lend support to the use of early genetic testing of at-risk individuals and families.\n\nFUNDING\nCanadian Cancer Society Research Institute, Canadian Institutes of Health Research, SickKids Foundation, and Soccer for Hope.", "authors": [ "Villani, A", "Tabori, U", "Schiffman, J", "Shlien, A", "Beyene, J", "Druker, H", "Novokmet, A", "Finlay, J", "Malkin, D" ], "is_common_article": false, "date_published": 20110600, "date_completed": 20110804, "format": "Article", "pub_med_id": 21601526, "title": "Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study.", "journal": "The Lancet. Oncology", "journal_abbreviation": "Lancet Oncol.", "journal_issue": "volume:12, issue:6" }, "14514923": { "abstract": "AIMS\nTo evaluate the usefulness of molecular markers in predicting histopathological and clinical response to preoperative high dose chemotherapy (HDCT) and survival of patients with advanced gastric cancer.\n\nMETHODS\nIn a phase II trial, 25 patients with metastatic gastric cancer received preoperative tandem HDCT consisting of etoposide, cisplatin, and mitomycin, followed by autologous bone marrow transplantation to achieve surgical resectability. Samples before and after treatment, from normal and tumour tissue, were characterised histopathologically, and both p53 and BAX expression was analysed by immunohistochemistry. Pretreatment formalin fixed, paraffin wax embedded samples from normal and tumour tissue were microdissected, and the extracted DNA was preamplified using improved primer extension preamplification polymerase chain reaction. Detection of microsatellite instability (MSI) or loss of heterozygosity (LOH) was performed using markers for p53, BAX, BAT25, BAT26, D2S123, D17S250, and APC. Exons 5-9 of the p53 gene were sequenced directly on ABI 373.\n\nRESULTS\nFour parameters were significantly associated with response to chemotherapy and prolonged overall survival: positive p53 immunostaining, positive p53 mutation status before chemotherapy, strong histological regression induced by preoperative HDCT, and surgical treatment. Patients's sex or age, tumour location or stage, lymph node status, Lauren classification, MSI, or LOH did not influence duration of survival significantly in this high risk population.\n\nCONCLUSION\nPositive p53 immunostaining and p53 mutation status in pretreatment tumour biopsies might be useful molecular predictors of response and prognosis in patients with advanced gastric cancer treated by preoperative HDCT.", "authors": [ "Bataille, F", "Rümmele, P", "Dietmaier, W", "Gaag, D", "Klebl, F", "Reichle, A", "Wild, P", "Hofstädter, F", "Hartmann, A" ], "is_common_article": false, "date_published": 20031000, "date_completed": 20040202, "format": "Article", "pub_med_id": 14514923, "title": "Alterations in p53 predict response to preoperative high dose chemotherapy in patients with gastric cancer.", "journal": "Molecular pathology : MP", "journal_abbreviation": "MP, Mol. Pathol.", "journal_issue": "volume:56, issue:5" }, "21747090": { "abstract": "PURPOSE\nIn the clinical management of children with relapsed acute lymphoblastic leukemia (ALL), treatment resistance remains a major challenge. Alterations of the TP53 gene are frequently associated with resistance to chemotherapy, but their significance in relapsed childhood ALL has remained controversial because of small studies.\n\nPATIENTS AND METHODS\nTherefore, we systematically studied 265 first-relapse patients enrolled in the German Acute Lymphoblastic Leukemia Relapse Berlin-Frankfurt-Mü nster 2002 (ALL-REZ BFM 2002) trial for sequence and copy number alterations of the TP53 gene by using direct sequencing and multiplex ligation-dependent probe amplification.\n\nRESULTS\nWe observed copy number and sequence alterations of TP53 in 12.4% (27 of 218) of patients with B-cell precursor ALL and 6.4% (three of 47) of patients with T-cell ALL relapse. Backtracking to initial ALL in 23 matched samples revealed that 54% of all TP53 alterations were gained at relapse. Within B-cell precursor ALL, TP53 alterations were consistently associated with nonresponse to chemotherapy (P < .001) and poor event-free survival (P < .001) and overall survival rates (P = .002). TP53 alterations also had a significant impact on survival within intermediate-risk (S2) and high-risk (S3/S4) relapse patients (P = .007 and P = .019, respectively). This prognostic significance of TP53 alterations was confirmed in multivariate analysis. Besides their clinical impact, TP53 alterations were associated with a higher fraction of leukemic cells in S/G(2)-M phase of the cell cycle at relapse diagnosis.\n\nCONCLUSION\nAlterations of the TP53 gene are of particular importance in the relapse stage of childhood ALL, in which they independently predict high risk of treatment failure in a significant number of patients. Therefore, they will aid in future risk assessment of children with ALL relapse.", "authors": [ "Hof, J", "Krentz, S", "van Schewick, C", "Körner, G", "Shalapour, S", "Rhein, P", "Karawajew, L", "Ludwig, WD", "Seeger, K", "Henze, G", "von Stackelberg, A", "Hagemeier, C", "Eckert, C", "Kirschner-Schwabe, R" ], "is_common_article": false, "date_published": 20110810, "date_completed": 20111005, "format": "Article", "pub_med_id": 21747090, "title": "Mutations and deletions of the TP53 gene predict nonresponse to treatment and poor outcome in first relapse of childhood acute lymphoblastic leukemia.", "journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", "journal_abbreviation": "J. Clin. Oncol.", "journal_issue": "volume:29, issue:23" }, "21837677": { "abstract": "BACKGROUND\nSarcoma is the index diagnosis of Li-Fraumeni syndrome (LFS), a familial predisposition to cancer that also includes brain cancer, breast cancer, and adrenal cortical carcinoma. Germline mutations in the TP53 gene are detected in approximately 80% of families that fulfill LFS criteria and in 15% to 25% of families that fulfill criteria for Li-Fraumeni-like syndrome (LFS), a group of related syndromes with broader clinical criteria.\n\nMETHODS\nThe authors of this report used the International Agency for Research on Cancer TP53 database to analyze the types, age at onset and mutation patterns of sarcoma in TP53 mutation carriers. Those data were compared with sarcoma types in the general population of Caucasians using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program.\n\nRESULTS\nOverall, sarcomas represented 25% of tumors in TP53 mutation carriers, and 95.6% occurred before age 50 years compared with 38.3% before age 50 years in the SEER data set. Sarcomas were more likely to be rhabdomyosarcoma in carriers aged <5 years (odds ratio [OR], 11.6; 95% confidence interval [CI], 6.1-21.9) and osteosarcoma in carriers at any age (aged <20 years: OR, 1.41; 95% CI, 1.02-1.94; age >20 years: OR, 4.61; 95% CI, 2.72-7.83). Early sarcoma (at age <20 years) was associated with missense mutations in exons encoding the DNA-binding domain of p53 protein. Conversely, p53 null mutations (frameshift, splice sites, nonsense) and mutations outside the DNA-binding domain were associated with leiomyosarcoma (OR, 10.1; 95% CI, 3.4-29.9), a type of sarcoma that occurred after age 20 years.\n\nCONCLUSIONS\nThe current results further demonstrated genotype-phenotype correlations and age-dependent variations in sarcoma types in carriers of germline TP53 mutations.", "authors": [ "Ognjanovic, S", "Olivier, M", "Bergemann, TL", "Hainaut, P" ], "is_common_article": false, "date_published": 20120301, "date_completed": 20120430, "format": "Article", "pub_med_id": 21837677, "title": "Sarcomas in TP53 germline mutation carriers: a review of the IARC TP53 database.", "journal": "Cancer", "journal_abbreviation": "Cancer", "journal_issue": "volume:118, issue:5" }, "21946351": { "abstract": "To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10(-17)), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10(-20)). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10(-6)), glioma (OR = 2.35, P = 1.0 × 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 × 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).", "authors": [ "Stacey, SN", "Sulem, P", "Jonasdottir, A", "Masson, G", "Gudmundsson, J", "Gudbjartsson, DF", "Magnusson, OT", "Gudjonsson, SA", "Sigurgeirsson, B", "Thorisdottir, K", "Ragnarsson, R", "Benediktsdottir, KR", "Nexø, BA", "Tjønneland, A", "Overvad, K", "Rudnai, P", "Gurzau, E", "Koppova, K", "Hemminki, K", "Corredera, C", "Fuentelsaz, V", "Grasa, P", "Navarrete, S", "Fuertes, F", "García-Prats, MD", "Sanambrosio, E", "Panadero, A", "De Juan, A", "Garcia, A", "Rivera, F", "Planelles, D", "Soriano, V", "Requena, C", "Aben, KK", "van Rossum, MM", "Cremers, RG", "van Oort, IM", "van Spronsen, DJ", "Schalken, JA", "Peters, WH", "Helfand, BT", "Donovan, JL", "Hamdy, FC", "Badescu, D", "Codreanu, O", "Jinga, M", "Csiki, IE", "Constantinescu, V", "Badea, P", "Mates, IN", "Dinu, DE", "Constantin, A", "Mates, D", "Kristjansdottir, S", "Agnarsson, BA", "Jonsson, E", "Barkardottir, RB", "Einarsson, GV", "Sigurdsson, F", "Moller, PH", "Stefansson, T", "Valdimarsson, T", "Johannsson, OT", "Sigurdsson, H", "Jonsson, T", "Jonasson, JG", "Tryggvadottir, L", "Rice, T", "Hansen, HM", "Xiao, Y", "Lachance, DH", "O Neill, BP", "Kosel, ML", "Decker, PA", "Thorleifsson, G", "Johannsdottir, H", "Helgadottir, HT", "Sigurdsson, A", "Steinthorsdottir, V", "Lindblom, A", "Sandler, RS", "Keku, TO", "Banasik, K", "Jørgensen, T", "Witte, DR", "Hansen, T", "Pedersen, O", "Jinga, V", "Neal, DE", "Catalona, WJ", "Wrensch, M", "Wiencke, J", "Jenkins, RB", "Nagore, E", "Vogel, U", "Kiemeney, LA", "Kumar, R", "Mayordomo, JI", "Olafsson, JH", "Kong, A", "Thorsteinsdottir, U", "Rafnar, T", "Stefansson, K" ], "is_common_article": false, "date_published": 20110925, "date_completed": 20111219, "format": "Article", "pub_med_id": 21946351, "title": "A germline variant in the TP53 polyadenylation signal confers cancer susceptibility.", "journal": "Nature genetics", "journal_abbreviation": "Nat. Genet.", "journal_issue": "volume:43, issue:11" }, "21990040": { "abstract": "BACKGROUND\nChoroid plexus tumors (CPT) are rare, and predominate in early childhood. An association with the Li-Fraumeni syndrome (LFS) has been reported, but the biological and clinical implications of this association remain poorly defined. We have investigated the clinical features and overall survival of all CPT patients treated at Children's Hospital Los Angeles (CHLA) over a 20-year period, with particular attention to the association of CPT with LFS.\n\nMETHODS\nA retrospective evaluation of the course of therapy and clinical outcome was undertaken on the 42 patients diagnosed with and treated for CPT at CHLA from January 1991 to December 2010. Any association with multiple primary tumors and family histories consistent with LFS was investigated in all patients.\n\nRESULTS\nSix of the 42 patients (16.7%), demonstrated either phenotypic and/or genotypic characteristics consistent with LFS, with either a distinct family history of cancer, a synchronous diagnosis of a different type of cancer, or the subsequent development of metachronous cancers. Of 11 patients with choroid plexus carcinoma tested for TP53 germline mutations, four (36.4%) were positive. A single patient with a choroid plexus papilloma had phenotypic characteristics of LFS but tested negative for TP53.\n\nCONCLUSIONS\nChildren with CPC appear to have a high frequency of TP53 germline mutations in association with LFS. This raises the question whether all children with CPC should be tested for TP53 germline mutations in order to institute screening to enhance early detection and treatment of subsequent cancers.", "authors": [ "Gozali, AE", "Britt, B", "Shane, L", "Gonzalez, I", "Gilles, F", "McComb, JG", "Krieger, MD", "Lavey, RS", "Shlien, A", "Villablanca, JG", "Erdreich-Epstein, A", "Dhall, G", "Jubran, R", "Tabori, U", "Malkin, D", "Finlay, JL" ], "is_common_article": false, "date_published": 20120600, "date_completed": 20120516, "format": "Article", "pub_med_id": 21990040, "title": "Choroid plexus tumors; management, outcome, and association with the Li-Fraumeni syndrome: the Children's Hospital Los Angeles (CHLA) experience, 1991-2010.", "journal": "Pediatric blood & cancer", "journal_abbreviation": "Pediatr Blood Cancer", "journal_issue": "volume:58, issue:6" }, "24487413": { "abstract": "To clarify the cooperative roles of recurrently identified mutations and to establish a more precise risk classification system in acute myeloid leukemia (AML), we comprehensively analyzed mutations in 51 genes, as well as cytogenetics and 11 chimeric transcripts, in 197 adult patients with de novo AML who were registered in the Japan Adult Leukemia Study Group AML201 study. We identified a total of 505 mutations in 44 genes, while only five genes, FLT3, NPM1, CEBPA, DNMT3A and KIT, were mutated in more than 10% of the patients. Although several cooperative and exclusive mutation patterns were observed, the accumulated mutation number was higher in cytogenetically normal AML and lower in AML with RUNX1-RUNX1T1 and CBFB-MYH11, indicating a strong potential of these translocations for the initiation of AML. Furthermore, we evaluated the prognostic impacts of each sole mutation and the combinations of mutations and/or cytogenetics, and demonstrated that AML patients could be clearly stratified into five risk groups for overall survival by including the mutation status of DNMT3A, MLL-PTD and TP53 genes in the risk classification system of the European LeukemiaNet. These results indicate that the prognosis of AML could be stratified by the major mutation status in combination with cytogenetics.", "authors": [ "Kihara, R", "Nagata, Y", "Kiyoi, H", "Kato, T", "Yamamoto, E", "Suzuki, K", "Chen, F", "Asou, N", "Ohtake, S", "Miyawaki, S", "Miyazaki, Y", "Sakura, T", "Ozawa, Y", "Usui, N", "Kanamori, H", "Kiguchi, T", "Imai, K", "Uike, N", "Kimura, F", "Kitamura, K", "Nakaseko, C", "Onizuka, M", "Takeshita, A", "Ishida, F", "Suzushima, H", "Kato, Y", "Miwa, H", "Shiraishi, Y", "Chiba, K", "Tanaka, H", "Miyano, S", "Ogawa, S", "Naoe, T" ], "is_common_article": false, "date_published": 20140800, "date_completed": 20141007, "format": "Article", "pub_med_id": 24487413, "title": "Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients.", "journal": "Leukemia", "journal_abbreviation": "Leukemia", "journal_issue": "volume:28, issue:8" }, "22090360": { "abstract": "PURPOSE\nMortality of patients with head and neck squamous cell carcinoma (HNSCC) is primarily driven by tumor cell radioresistance leading to locoregional recurrence (LRR). In this study, we use a classification of TP53 mutation (disruptive vs. nondisruptive) and examine impact on clinical outcomes and radiation sensitivity.\n\nEXPERIMENTAL DESIGN\nSeventy-four patients with HNSCC treated with surgery and postoperative radiation and 38 HNSCC cell lines were assembled; for each, TP53 was sequenced and the in vitro radioresistance measured using clonogenic assays. p53 protein expression was inhibited using short hairpin RNA (shRNA) and overexpressed using a retrovirus. Radiation-induced apoptosis, mitotic cell death, senescence, and reactive oxygen species (ROS) assays were carried out. The effect of the drug metformin on overcoming mutant p53-associated radiation resistance was examined in vitro as well as in vivo, using an orthotopic xenograft model.\n\nRESULTS\nMutant TP53 alone was not predictive of LRR; however, disruptive TP53 mutation strongly predicted LRR (P = 0.03). Cell lines with disruptive mutations were significantly more radioresistant (P < 0.05). Expression of disruptive TP53 mutations significantly decreased radiation-induced senescence, as measured by SA-β-gal staining, p21 expression, and release of ROS. The mitochondrial agent metformin potentiated the effects of radiation in the presence of a disruptive TP53 mutation partially via senescence. Examination of our patient cohort showed that LRR was decreased in patients taking metformin.\n\nCONCLUSIONS\nDisruptive TP53 mutations in HNSCC tumors predicts for LRR, because of increased radioresistance via the inhibition of senescence. Metformin can serve as a radiosensitizer for HNSCC with disruptive TP53, presaging the possibility of personalizing HNSCC treatment.", "authors": [ "Skinner, HD", "Sandulache, VC", "Ow, TJ", "Meyn, RE", "Yordy, JS", "Beadle, BM", "Fitzgerald, AL", "Giri, U", "Ang, KK", "Myers, JN" ], "is_common_article": false, "date_published": 20120101, "date_completed": 20120409, "format": "Article", "pub_med_id": 22090360, "title": "TP53 disruptive mutations lead to head and neck cancer treatment failure through inhibition of radiation-induced senescence.", "journal": "Clinical cancer research : an official journal of the American Association for Cancer Research", "journal_abbreviation": "Clin. Cancer Res.", "journal_issue": "volume:18, issue:1" }, "22170717": { "abstract": "CONTEXT\nLi-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with germline mutations in TP53. According to the Chompret criteria for LFS, any patient with adrenocortical cancer (ACC), irrespective of age and family history, is at high risk for a TP53 germline mutation. However, whereas such mutations have been detected with high frequency in childhood ACC, a large cohort of adult patients with ACC has never been investigated for TP53 germline mutations.\n\nOBJECTIVE\nThe aim of the study was to evaluate the prevalence of TP53 germline mutations in adult patients with ACC.\n\nSUBJECTS AND METHODS\nIn 103 adult Caucasian patients with ACC, TP53 germline mutation analysis was performed. In patients with a TP53 germline mutation, tumor tissue was analyzed for loss of heterozygosity of TP53 and p53 immunohistochemistry. Family history and clinical course were also evaluated.\n\nRESULTS\nIn four patients, a total of five TP53 germline mutations were found. Two mutations occurred in exon 10 (R337H and I332M, respectively), outside the hot spot region. Here, three mutations are described for the first time in ACC, and one, which occurred combined with a second mutation (R202C) on the same allele, has never been reported before in the context of LFS. This combined mutation was associated with a remarkable family history of ACC also affecting the mother and uncle of the index patient. In the 23 patients with ACC below the age of 40 yr, 13% (95% confidence interval, 3.7-32.9%) carried a TP53 germline mutation, whereas such mutations were rare in older patients with ACC.\n\nCONCLUSION\nOur findings indicate a need to revise the Chompret criteria. However, in younger adults (<40 yr old) with ACC, screening for TP53 germline mutations may be justified.", "authors": [ "Herrmann, LJ", "Heinze, B", "Fassnacht, M", "Willenberg, HS", "Quinkler, M", "Reisch, N", "Zink, M", "Allolio, B", "Hahner, S" ], "is_common_article": false, "date_published": 20120300, "date_completed": 20120706, "format": "Article", "pub_med_id": 22170717, "title": "TP53 germline mutations in adult patients with adrenocortical carcinoma.", "journal": "The Journal of clinical endocrinology and metabolism", "journal_abbreviation": "J. Clin. Endocrinol. Metab.", "journal_issue": "volume:97, issue:3" }, "22425996": { "abstract": "Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.", "authors": [ "Chen, Z", "Cheng, K", "Walton, Z", "Wang, Y", "Ebi, H", "Shimamura, T", "Liu, Y", "Tupper, T", "Ouyang, J", "Li, J", "Gao, P", "Woo, MS", "Xu, C", "Yanagita, M", "Altabef, A", "Wang, S", "Lee, C", "Nakada, Y", "Peña, CG", "Sun, Y", "Franchetti, Y", "Yao, C", "Saur, A", "Cameron, MD", "Nishino, M", "Hayes, DN", "Wilkerson, MD", "Roberts, PJ", "Lee, CB", "Bardeesy, N", "Butaney, M", "Chirieac, LR", "Costa, DB", "Jackman, D", "Sharpless, NE", "Castrillon, DH", "Demetri, GD", "Jänne, PA", "Pandolfi, PP", "Cantley, LC", "Kung, AL", "Engelman, JA", "Wong, KK" ], "is_common_article": false, "date_published": 20120318, "date_completed": 20120508, "format": "Article", "pub_med_id": 22425996, "title": "A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response.", "journal": "Nature", "journal_abbreviation": "Nature", "journal_issue": "volume:483, issue:7391" }, "22551548": { "abstract": "INTRODUCTION\nThe Li-Fraumeni syndrome (LFS) is an autosomal dominant hereditary disorder associated with different tumor types in childhood and young adults. Approximately 70% of LFS cases contain germline mutations in the TP53 gene. We report a case of a family suspected of LFS.\n\nMATERIALS AND METHODS\nThe proband and four members of the family affected were diagnosed with cancer at an early age and they all died except the proband. Exons 5-9 from TP53 gene were analysed by direct amplification and sequencing in 7 family members.\n\nRESULTS\nThe analysis revealed a germline nonsense mutation in exon 8 at codon 306 of the codified region of the TP53 gene, causing a change of CGA to TGA (Arg→Stop) in the proband, her mother, her cousin and her maternal uncle. Proband's maternal grandmother and aunt do not have the mutation.\n\nCONCLUSIONS\nThe members of this family that were studied meet the criteria of classic LFS and the described mutation increases their susceptibility to develop cancer. The proband's maternal grandfather died of lung cancer in 1993, and we believe that he was the carrier of the mutation in this family.", "authors": [ "Aurtenetxe Sáez, O", "Calvo, B", "Fernández-Teijeiro, A", "Pérez, P", "Navajas, A" ], "is_common_article": false, "date_published": 20120500, "date_completed": 20120904, "format": "Article", "pub_med_id": 22551548, "title": "A prospective biological study in relation to a family with Li-Fraumeni syndrome.", "journal": "Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico", "journal_abbreviation": "Clin Transl Oncol", "journal_issue": "volume:14, issue:5" }, "22672556": { "abstract": "BACKGROUND\nLi-Fraumeni-Syndrome (LFS) is an autosomal-dominant, inherited tumour predisposition syndrome associated with heterozygous germline mutations in the TP53 gene. Patients with LFS are at a high risk to develop early-onset breast cancer and multiple malignancies, among which sarcomas are the most common. A high incidence of childhood tumours and close to 100% penetrance has been described. Knowledge of the genetic status of the TP53 gene in these patients is critical not only due to the increased risk of malignancies, but also because of the therapeutic implications, since a higher rate of radiation-induced secondary tumours in these patients has been observed.\n\nCASE REPORT\nWe report a patient with LFS harbouring heterozygous, pathogenic TP53 germline mutation, who was affected by four synchronous malignancies at the age of 40: a myxofibrosarcoma of the right upper arm, bilateral breast cancer and a periadrenal liposarcoma. Radiological treatments and a surveillance program were adjusted according to recommendations for LFS patients.\n\nCONCLUSION\nManagement of tumour treatment of patients with LFS is different to the general population because of their risk for secondary cancers in the radiation field. Screening procedures should take a possibly elevated risk for radiation induced cancer into account.", "authors": [ "Kast, K", "Krause, M", "Schuler, M", "Friedrich, K", "Thamm, B", "Bier, A", "Distler, W", "Krüger, S" ], "is_common_article": false, "date_published": 20120606, "date_completed": 20130617, "format": "Article", "pub_med_id": 22672556, "title": "Late onset Li-Fraumeni Syndrome with bilateral breast cancer and other malignancies: case report and review of the literature.", "journal": "BMC cancer", "journal_abbreviation": "BMC Cancer", "journal_issue": "volume:12" }, "27463065": { "abstract": "BACKGROUND\nMutations in the tumor protein 53 (TP53) gene predict a poor prognosis in patients with acute myeloid leukemia (AML).\n\nMETHODS\nPeripheral blood or bone marrow samples from 293 patients with newly diagnosed AML were analyzed with targeted, amplicon-based, next-generation sequencing-based mutation analysis.\n\nRESULTS\nTP53 mutations were identified in 53 patients (18%; 45 were missense mutations). In 13 of the 53 patients, the most common pattern of amino acid substitution was a substitution of arginine to histidine on different codons. The clinical characteristics, pattern of mutations, response to different therapies, and outcomes of patients with AML-TP53-mutated (n = 53) versus wild-type TP53 (n = 240) were compared. TP53 mutations were significantly more likely in patients who had a complex karyotype; abnormalities of chromosome 5, 7, and 17; and therapy-related AML. Patients who had TP53-mutated AML had significantly lower incidence of mutations in Fms-like tyrosine kinase 3 (FLT3), rat sarcoma (RAS), and nucleophosmin (NPM1) and higher incidence of coexisting MPL mutations compared with those who had wild type TP53. The distribution of TP53 mutations was equal for both age groups (ages <60 years vs ≥60 years). TP53-mutated AML was associated with a lower complete remission rate (41% vs 57%; P = .04), a significantly inferior complete remission duration (at 2 years: 30% vs 55%; P = .001), and overall survival (at 2 years: 9% vs 24%; P ≤ .0001) irrespective of age or the type of treatment received (high-intensity vs low-intensity chemotherapy).\n\nCONCLUSIONS\nThe type of treatment received did not improve outcomes in younger or older patients with TP53-mutated AML. These data suggest that novel therapies are needed to improve the outcome of patients with AML who have TP53 mutations. Cancer 2016;122:3484-3491. © 2016 American Cancer Society.", "authors": [ "Kadia, TM", "Jain, P", "Ravandi, F", "Garcia-Manero, G", "Andreef, M", "Takahashi, K", "Borthakur, G", "Jabbour, E", "Konopleva, M", "Daver, NG", "Dinardo, C", "Pierce, S", "Kanagal-Shamanna, R", "Patel, K", "Estrov, Z", "Cortes, J", "Kantarjian, HM" ], "is_common_article": false, "date_published": 20161115, "date_completed": 0, "format": "Article", "pub_med_id": 27463065, "title": "TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes.", "journal": "Cancer", "journal_abbreviation": "Cancer", "journal_issue": "volume:122, issue:22" }, "24725250": { "authors": [ "Malcikova, J", "Stalika, E", "Davis, Z", "Plevova, K", "Trbusek, M", "Mansouri, L", "Scarfò, L", "Baliakas, P", "Gardiner, A", "Sutton, LA", "Francova, HS", "Agathangelidis, A", "Anagnostopoulos, A", "Tracy, I", "Makris, A", "Smardova, J", "Ghia, P", "Belessi, C", "Gonzalez, D", "Rosenquist, R", "Oscier, D", "Pospisilova, S", "Stamatopoulos, K" ], "is_common_article": false, "date_published": 20140800, "date_completed": 20140918, "format": "Article", "pub_med_id": 24725250, "title": "The frequency of TP53 gene defects differs between chronic lymphocytic leukaemia subgroups harbouring distinct antigen receptors.", "journal": "British journal of haematology", "journal_abbreviation": "Br. J. Haematol.", "journal_issue": "volume:166, issue:4" }, "22698404": { "abstract": "Studies on the role of TP53 mutation in breast cancer response to chemotherapy are conflicting. Here, we show that, contrary to dogma, MMTV-Wnt1 mammary tumors with mutant p53 exhibited a superior clinical response compared to tumors with wild-type p53. Doxorubicin-treated p53 mutant tumors failed to arrest proliferation, leading to abnormal mitoses and cell death, whereas p53 wild-type tumors arrested, avoiding mitotic catastrophe. Senescent tumor cells persisted, secreting senescence-associated cytokines exhibiting autocrine/paracrine activity and mitogenic potential. Wild-type p53 still mediated arrest and inhibited drug response even in the context of heterozygous p53 point mutations or absence of p21. Thus, we show that wild-type p53 activity hinders chemotherapy response and demonstrate the need to reassess the paradigm for p53 in cancer therapy.", "authors": [ "Jackson, JG", "Pant, V", "Li, Q", "Chang, LL", "Quintás-Cardama, A", "Garza, D", "Tavana, O", "Yang, P", "Manshouri, T", "Li, Y", "El-Naggar, AK", "Lozano, G" ], "is_common_article": false, "date_published": 20120612, "date_completed": 20120831, "format": "Article", "pub_med_id": 22698404, "title": "p53-mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer.", "journal": "Cancer cell", "journal_abbreviation": "Cancer Cell", "journal_issue": "volume:21, issue:6" }, "22699455": { "abstract": "Despite risk-adapted treatment, survival of children with relapse of acute lymphoblastic leukemia (ALL) remains poor compared with that of patients with initial diagnosis of ALL. Leukemia-associated genetic alterations may provide novel prognostic factors to refine present relapse treatment strategies. Therefore, we investigated the clinical relevance of 13 recurrent genetic alterations in 204 children treated uniformly for relapsed B-cell precursor ALL according to the ALL-REZ BFM 2002 protocol. The most common alterations were deletions of CDKN2A/2B, IKZF1, PAX5, ETV6, fusion of ETV6-RUNX1 and deletions and/or mutations of TP53. Multivariate analysis identified IKZF1 deletion and TP53 alteration as independent predictors of inferior outcome (P=0.002 and P=0.001). Next, we investigated how both alterations can improve the established risk stratification in relapsed ALL. Intermediate-risk relapse patients with low minimal residual disease are currently considered to have a good prognosis. In this group, deletion of IKZF1 and alteration of TP53 identify patients with significantly inferior outcome (P<0.001). In high-risk relapse patients, deletion of IKZF1 is strongly predictive of a second relapse after stem cell transplantation (P<0.001). We conclude that IKZF1 and TP53 represent relevant prognostic factors that should be considered in future risk assessment of children with relapsed ALL to indicate treatment intensification or intervention.", "authors": [ "Krentz, S", "Hof, J", "Mendioroz, A", "Vaggopoulou, R", "Dörge, P", "Lottaz, C", "Engelmann, JC", "Groeneveld, TW", "Körner, G", "Seeger, K", "Hagemeier, C", "Henze, G", "Eckert, C", "von Stackelberg, A", "Kirschner-Schwabe, R" ], "is_common_article": false, "date_published": 20130200, "date_completed": 20130404, "format": "Article", "pub_med_id": 22699455, "title": "Prognostic value of genetic alterations in children with first bone marrow relapse of childhood B-cell precursor acute lymphoblastic leukemia.", "journal": "Leukemia", "journal_abbreviation": "Leukemia", "journal_issue": "volume:27, issue:2" }, "22878818": { "abstract": "Li-Fraumeni syndrome (LFS) is one of the most penetrant forms of familial cancer susceptibility syndromes, characterized by early age at tumor onset and a wide spectrum of malignant tumors. Identifying LFS in patients with cancer is clinically imperative because they have an increased sensitivity to ionizing radiation and are more likely to develop radiation-induced secondary malignancies. This case report describes a young woman whose initial presentation of LFS was early-onset breast cancer and whose treatment of this primary malignancy with breast conservation likely resulted in a secondary malignancy arising in her radiation field. As seen in this case, most breast cancers in patients with LFS exhibit a triple-positive phenotype (estrogen receptor-positive/progesterone receptor-positive/HER2-positive). Although this patient met classic LFS criteria based on age and personal and family history of cancer, the NCCN Clinical Practice Guidelines in Oncology for Genetic/Familial High-Risk Assessment: Breast and Ovarian Cancer endorse genetic screening for TP53 mutations in a subset of patients with early-onset breast cancer, even in the absence of a suggestive family history, because of the potential for de novo TP53 mutations.", "authors": [ "Henry, E", "Villalobos, V", "Million, L", "Jensen, KC", "West, R", "Ganjoo, K", "Lebensohn, A", "Ford, JM", "Telli, ML" ], "is_common_article": false, "date_published": 20120800, "date_completed": 20130117, "format": "Article", "pub_med_id": 22878818, "title": "Chest wall leiomyosarcoma after breast-conservative therapy for early-stage breast cancer in a young woman with Li-Fraumeni syndrome.", "journal": "Journal of the National Comprehensive Cancer Network : JNCCN", "journal_abbreviation": "J Natl Compr Canc Netw", "journal_issue": "volume:10, issue:8" }, "22939227": { "abstract": "Li-Fraumeni syndrome (LFS) is a rare dominantly inherited cancer predisposition syndrome that was first described in 1969. In most families, it is caused by germline mutations in the TP53 gene and is characterized by early onset of multiple specific cancers and very high lifetime cumulative cancer risk. Despite significant progress in understanding the molecular biology of TP53, the optimal clinical management of this syndrome is poorly defined. We convened a workshop on November 2, 2010, at the National Institutes of Health in Bethesda, Maryland, bringing together clinicians and scientists, as well as individuals from families with LFS, to review the state of the science, address clinical management issues, stimulate collaborative research, and engage the LFS family community. This workshop also led to the creation of the Li-Fraumeni Exploration (LiFE) Research Consortium.", "authors": [ "Mai, PL", "Malkin, D", "Garber, JE", "Schiffman, JD", "Weitzel, JN", "Strong, LC", "Wyss, O", "Locke, L", "Means, V", "Achatz, MI", "Hainaut, P", "Frebourg, T", "Evans, DG", "Bleiker, E", "Patenaude, A", "Schneider, K", "Wilfond, B", "Peters, JA", "Hwang, PM", "Ford, J", "Tabori, U", "Ognjanovic, S", "Dennis, PA", "Wentzensen, IM", "Greene, MH", "Fraumeni, JF", "Savage, SA" ], "is_common_article": false, "date_published": 20121000, "date_completed": 20130110, "format": "Article", "pub_med_id": 22939227, "title": "Li-Fraumeni syndrome: report of a clinical research workshop and creation of a research consortium.", "journal": "Cancer genetics", "journal_abbreviation": "Cancer Genet", "journal_issue": "volume:205, issue:10" }, "11325447": { "abstract": "BACKGROUND AND METHODS\nTP53 gene-mutation and expression of p53 have been described to influence the radiosensitivity of tumour cells from head and neck carcinomas. The present study was performed to evaluate whether TP53 mutation may influence the clinical outcome of head and neck cancer patients treated with radiotherapy or surgery.\n\nMATERIALS AND METHODS\nDNA was extracted from formalin-fixed paraffin-embedded tissue sections from primary biopsies taken before radiotherapy. Gene mutations (in exons 5-9) were identified using denaturing gradient gel electrophoresis (DGGE) as the initial scanning procedure and characterized by sequencing. Patients were treated with primary radiotherapy or surgery alone. Treatment was given according to the DAHANCA schedules with 5 or 6 weekly fractions (2 Gy) of radiotherapy (66-68 Gy). Most patients were also treated with the hypoxic radiosensitizer Nimorazole. The results are reported as 5-year actuarial values, and differences estimated by log-rank analysis.\n\nRESULTS\nThe present analysis is based on 114 patients with squamous cell carcinoma of the larynx, pharynx and oral cavity diagnosed between March 1992 and October 1996. Ninety patients received primary radiotherapy alone and 21 were treated with surgery. TP53 mutations were found in 45 patients (39%) and in patients receiving radiotherapy, TP53 mutation was highly associated with poor prognosis. Loco-regional control rates (5-year actuarial values) for TP53 mutation was 29 vs. 54% for TP53 wildtype (P < 0.01). For disease-free survival the corresponding values were 13 and 38% (P < 0.01), respectively. The correlations were not found to be related to specific subtypes of mutations (e.g. missense mutations affecting DNA-contact or Zn-binding regions) but rather to the presence of any mutation at all. In contrast, TP53 mutation did not influence the response to surgery.\n\nCONCLUSIONS\nA strong relationship was observed between TP53 mutation and poor prognosis (increased risk of loco-regional failure and death) in head and neck cancer patients given primary radiotherapy but not surgery.", "authors": [ "Alsner, J", "Sørensen, SB", "Overgaard, J" ], "is_common_article": false, "date_published": 20010500, "date_completed": 20010913, "format": "Article", "pub_med_id": 11325447, "title": "TP53 mutation is related to poor prognosis after radiotherapy, but not surgery, in squamous cell carcinoma of the head and neck.", "journal": "Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology", "journal_abbreviation": "Radiother Oncol", "journal_issue": "volume:59, issue:2" }, "23015295": { "abstract": "BACKGROUND\nGastric adenocarcinoma is a rare diagnosis in childhood. A 14-year-old male patient presented with metastatic gastric adenocarcinoma, and a strong family history of colon cancer. Clinical sequencing of CDH1 and APC were negative. Whole exome sequencing was therefore applied to capture the majority of protein-coding regions for the identification of single-nucleotide variants, small insertion/deletions, and copy number abnormalities in the patient's germline as well as primary tumor.\n\nMATERIALS AND METHODS\nDNA was extracted from the patient's blood, primary tumor, and the unaffected mother's blood. DNA libraries were constructed and sequenced on Illumina HiSeq2000. Data were post-processed using Picard and Samtools, then analyzed with the Genome Analysis Toolkit. Variants were annotated using an in-house Ensembl-based program. Copy number was assessed using ExomeCNV.\n\nRESULTS\nEach sample was sequenced to a mean depth of coverage of greater than 120×. A rare non-synonymous coding single-nucleotide variant (SNV) in TP53 was identified in the germline. There were 10 somatic cancer protein-damaging variants that were not observed in the unaffected mother genome. ExomeCNV comparing tumor to the patient's germline, identified abnormal copy number, spanning 6,946 genes.\n\nCONCLUSION\nWe present an unusual case of Li-Fraumeni detected by whole exome sequencing. There were also likely driver somatic mutations in the gastric adenocarcinoma. These results highlight the need for more thorough and broad scale germline and cancer analyses to accurately inform patients of inherited risk to cancer and to identify somatic mutations.", "authors": [ "Chang, VY", "Federman, N", "Martinez-Agosto, J", "Tatishchev, SF", "Nelson, SF" ], "is_common_article": false, "date_published": 20130400, "date_completed": 20130417, "format": "Article", "pub_med_id": 23015295, "title": "Whole exome sequencing of pediatric gastric adenocarcinoma reveals an atypical presentation of Li-Fraumeni syndrome.", "journal": "Pediatric blood & cancer", "journal_abbreviation": "Pediatr Blood Cancer", "journal_issue": "volume:60, issue:4" }, "23297687": { "abstract": "This study aimed to determine the incidence/prognostic impact of TP53 mutation in 318 myelodysplastic syndrome (MDS) patients, and to correlate the changes to cytogenetics, single nucleotide polymorphism array karyotyping and clinical outcome. The median age was 65 years (17-89 years) and median follow-up was 45 months [95% confidence interval (CI) 27-62 months]. TP53 mutations occurred in 30 (9.4%) patients, exclusively in isolated del5q (19%) and complex karyotype (CK) with -5/5q-(72%), correlated with International Prognostic Scoring System intermediate-2/high, TP53 protein expression, higher blast count and leukaemic progression. Patients with mutant TP53 had a paucity of mutations in other genes implicated in myeloid malignancies. Median overall survival of patients with TP53 mutation was shorter than wild-type (9 versus 66 months, P < 0.001) and it retained significance in multivariable model (Hazard Ratio 3.8, 95%CI 2.3-6.3,P < 0.001). None of the sequentially analysed samples showed a disappearance of the mutant clone or emergence of new clones, suggesting an early occurrence of TP53 mutations. A reduction in mutant clone correlated with response to 5-azacitidine, however clones increased in non-responders and persisted at relapse. The adverse impact of TP53 persists after adjustment for cytogenetic risk and is of practical importance in evaluating prognosis. The relatively common occurrence of these mutations in two different prognostic spectrums of MDS, i.e. isolated 5q- and CK with -5/5q-, possibly implies two different mechanistic roles for TP53 protein.", "authors": [ "Kulasekararaj, AG", "Smith, AE", "Mian, SA", "Mohamedali, AM", "Krishnamurthy, P", "Lea, NC", "Gäken, J", "Pennaneach, C", "Ireland, R", "Czepulkowski, B", "Pomplun, S", "Marsh, JC", "Mufti, GJ" ], "is_common_article": false, "date_published": 20130300, "date_completed": 20130412, "format": "Article", "pub_med_id": 23297687, "title": "TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis.", "journal": "British journal of haematology", "journal_abbreviation": "Br. J. Haematol.", "journal_issue": "volume:160, issue:5" }, "24072100": { "abstract": "Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a very rare disease that currently lacks genomic and genetic biomarkers to assist in its clinical management. We performed whole-exome sequencing (WES) of three BPDCN cases. Based on these data, we designed a resequencing approach to identify mutations in 38 selected genes in 25 BPDCN samples. WES revealed 37-99 deleterious gene mutations per exome with no common affected genes between patients, but with clear overlap in terms of molecular and disease pathways (hematological and dermatological disease). We identified for the first time deleterious mutations in IKZF3, HOXB9, UBE2G2 and ZEB2 in human leukemia. Target sequencing identified 29 recurring genes, ranging in prevalence from 36% for previously known genes, such as TET2, to 12-16% for newly identified genes, such as IKZF3 or ZEB2. Half of the tumors had mutations affecting either the DNA methylation or chromatin remodeling pathways. The clinical analysis revealed that patients with mutations in DNA methylation pathway had a significantly reduced overall survival (P=0.047). We provide the first mutational profiling of BPDCN. The data support the current WHO classification of the disease as a myeloid disorder and provide a biological rationale for the incorporation of epigenetic therapies for its treatment.", "authors": [ "Menezes, J", "Acquadro, F", "Wiseman, M", "Gómez-López, G", "Salgado, RN", "Talavera-Casañas, JG", "Buño, I", "Cervera, JV", "Montes-Moreno, S", "Hernández-Rivas, JM", "Ayala, R", "Calasanz, MJ", "Larrayoz, MJ", "Brichs, LF", "Gonzalez-Vicent, M", "Pisano, DG", "Piris, MA", "lvarez, S", "Cigudosa, JC" ], "is_common_article": false, "date_published": 20140400, "date_completed": 20140616, "format": "Article", "pub_med_id": 24072100, "title": "Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm.", "journal": "Leukemia", "journal_abbreviation": "Leukemia", "journal_issue": "volume:28, issue:4" }, "23355100": { "abstract": "Prevalent as an acquired abnormality in cancer, the role of tumor protein p53 (TP53) as a germline mutation continues to evolve. The clinical impact of a germline TP53 mutation is often dramatic and affects the full life course, with a propensity to develop rare tumors in childhood and multiple common cancers of unexpectedly early onset in adulthood. In this article, we review the clinical relevance of germline mutations in the TP53 tumor suppressor gene to current healthcare practice, including the optimal ways to identify patients with Li-Fraumeni syndrome (LFS), to recognize the core cancers associated with LFS, and to develop strategies for early detection of LFS-associated tumors. Several TP53-targeted approaches to improve outcomes in LFS patients are also reviewed. A case report is used to highlight special TP53 testing dilemmas and unique challenges associated with genetic testing decisions in the current age of rapidly advancing genomic technologies.", "authors": [ "Sorrell, AD", "Espenschied, CR", "Culver, JO", "Weitzel, JN" ], "is_common_article": false, "date_published": 20130200, "date_completed": 20130809, "format": "Article", "pub_med_id": 23355100, "title": "Tumor protein p53 (TP53) testing and Li-Fraumeni syndrome : current status of clinical applications and future directions.", "journal": "Molecular diagnosis & therapy", "journal_abbreviation": "Mol Diagn Ther", "journal_issue": "volume:17, issue:1" }, "23403321": { "authors": [ "Chiaretti, S", "Brugnoletti, F", "Tavolaro, S", "Bonina, S", "Paoloni, F", "Marinelli, M", "Patten, N", "Bonifacio, M", "Kropp, MG", "Sica, S", "Guarini, A", "Foà, R" ], "is_common_article": false, "date_published": 20130500, "date_completed": 20131203, "format": "Article", "pub_med_id": 23403321, "title": "TP53 mutations are frequent in adult acute lymphoblastic leukemia cases negative for recurrent fusion genes and correlate with poor response to induction therapy.", "journal": "Haematologica", "journal_abbreviation": "Haematologica", "journal_issue": "volume:98, issue:5" }, "23409989": { "abstract": "We describe a 15-year-old girl with a novel germline p53 splice site mutation who developed an osteosarcoma. She received several cycles of chemotherapy with complete resection of the primary tumor without amputation, and has maintained remission for 18 months. Li-Fraumeni-like syndrome was suspected based on familial history. Sequence analysis revealed the presence of a novel germline p53 gene mutation resulting in a G to A transition at position +1 at the donor splice site of intron 6, creating a 6 amino acid insertion. This case provides interesting insight into the phenotype-genotype correlation in LFL syndrome with a TP53 splicing mutation.", "authors": [ "Sakurai, N", "Iwamoto, S", "Miura, Y", "Nakamura, T", "Matsumine, A", "Nishioka, J", "Nakatani, K", "Komada, Y" ], "is_common_article": false, "date_published": 20130200, "date_completed": 20131212, "format": "Article", "pub_med_id": 23409989, "title": "Novel p53 splicing site mutation in Li-Fraumeni-like syndrome with osteosarcoma.", "journal": "Pediatrics international : official journal of the Japan Pediatric Society", "journal_abbreviation": "Pediatr Int", "journal_issue": "volume:55, issue:1" }, "25952993": { "abstract": "BACKGROUND\nTP53 mutation is more prevalent in therapy-related myeloid neoplasms (t-MN) than their de novo counterparts; however, the pattern of mutations involving TP53 gene in t-MN versus de novo diseases is largely unknown.\n\nMETHODS\nWe collected 108 consecutive patients with therapy-related myelodysplastic syndrome (t-MDS)/acute myeloid leukemia (t-AML). Clinical, hematological, and cytogenetic data were collected by searching the electronic medical record. TP53 sequencing was performed in all patients using a clinically validated next-generation sequencing-based gene panel assay. A previously published patient cohort consisting of 428 patients with de novo MDS/AML was included for comparison.\n\nRESULTS\nWe assessed 108 patients with t-MN, in which 40 patients (37%) had TP53 mutations. The mutation frequency was similar between t-MDS and t-AML; but significantly higher than de novo MDS/AML (62/428 patients, 14.5%) (p<0.0001). TP53 mutations in t-MN were mainly clustered in DNA-binding domains, with an allelic frequency of 37.0% (range, 7.1 to 98.8). Most mutations involved single nucleotide changes, of which, transitions (65.9%) were more common than transversions (34.1%). Missense mutations were the most frequent, followed by frameshift and nonsense mutations. This TP53 mutation pattern was strikingly similar to that observed in de novo MDS/AML. TP53 mutations in t-MN were associated with a complex karyotype (p<0.0001), a higher number of chromosomal abnormalities (p<0.0001), and an inferior overall survival in affected patients (6.1 vs 14.1 months) by univariate (p<0.0001) and multivariate analyses (p=0.0020).\n\nCONCLUSIONS\nOur findings support the recent notion that heterozygous TP53 mutation may be a function of normal aging and that mutated cells are subject to selection upon exposure to cytotoxic therapy. t-MN carrying TP53 mutation have an aggressive clinical course independent of other confounding factors.", "authors": [ "Ok, CY", "Patel, KP", "Garcia-Manero, G", "Routbort, MJ", "Peng, J", "Tang, G", "Goswami, M", "Young, KH", "Singh, R", "Medeiros, LJ", "Kantarjian, HM", "Luthra, R", "Wang, SA" ], "is_common_article": false, "date_published": 20150508, "date_completed": 20160119, "format": "Article", "pub_med_id": 25952993, "title": "TP53 mutation characteristics in therapy-related myelodysplastic syndromes and acute myeloid leukemia is similar to de novo diseases.", "journal": "Journal of hematology & oncology", "journal_abbreviation": "J Hematol Oncol", "journal_issue": "volume:8" }, "23667851": { "abstract": "Li-Fraumeni syndrome (LFS) is a rare, inherited syndrome associated with increased risk of various early-onset tumors. Since the introduction of classic LFS criteria, various criteria have been proposed to include patients with incomplete LFS features, which make up Li-Fraumeni-like syndromes (LFL). Germline missense mutations of TP53 are the primary cause of LFS and LFL. Mutations mostly reside in the DNA-binding domain of the gene and have a dominant-negative effect (DNE) over alternate wild-type alleles. Germline TP53 mutation c.566C>T results in the missense mutation GCC (Ala) to GTC (Val) at codon 189 (A189V) and has been reported in a case of multiple primary colon tumors. Herein we report a second case of the same mutation in a breast cancer patient, who has familial history of late-onset malignancies. Due to the relatively late onset of malignancies, neither case fulfils previously defined criteria for the syndrome. Mutational analysis for breast tissue in this patient showed a loss of heterozygosity. These clinical features may suggest a relatively weak DNE of A189V compared to other TP53 mutations, and in silico predictions and in vitro findings of the function of A189V mutant protein are conflicting. Considering the increased risk of malignancies and the therapeutic implications for patients who have a TP53 mutation, care must be taken when treating those who are suspected of possessing cancer-prone traits due to TP53 mutation, especially when there is a family history of late-onset cancer with low penetrance.", "authors": [ "Cho, Y", "Kim, J", "Kim, Y", "Jeong, J", "Lee, KA" ], "is_common_article": false, "date_published": 20130500, "date_completed": 20131127, "format": "Article", "pub_med_id": 23667851, "title": "A case of late-onset Li-Fraumeni-like syndrome with unilateral breast cancer.", "journal": "Annals of laboratory medicine", "journal_abbreviation": "Ann Lab Med", "journal_issue": "volume:33, issue:3" } }, "identifiers": { "hgnc_previous_symbol": null, "hgnc_id": null, "uniprot_id": [ "A0A087WT22", "A0A087WXZ1", "A0A087WZU8", "A0A087X1Q1", "A0A0U1RQC9", "E7EMR6", "E7EQX7", "E7ESS1", "E9PCY9", "E9PFT5", "I3L0W9", "J3KP33", "P04637", "S4R334" ], "ensembl_id": null, "entrez_id": [ "7157" ], "lrg_id": [ "LRG_321" ] }, "ghr_genes": { "version": "09_jan_2020", "items": [ { "html_text": "The TP53 gene provides instructions for making a protein called tumor protein p53 (or p53). This protein acts as a tumor suppressor, which means that it regulates cell division by keeping cells from growing and dividing (proliferating) too fast or in an uncontrolled way.
The p53 protein is located in the nucleus of cells throughout the body, where it attaches (binds) directly to DNA. When the DNA in a cell becomes damaged by agents such as toxic chemicals, radiation, or ultraviolet (UV) rays from sunlight, this protein plays a critical role in determining whether the DNA will be repaired or the damaged cell will self-destruct (undergo apoptosis). If the DNA can be repaired, p53 activates other genes to fix the damage. If the DNA cannot be repaired, this protein prevents the cell from dividing and signals it to undergo apoptosis. By stopping cells with mutated or damaged DNA from dividing, p53 helps prevent the development of tumors.
Because p53 is essential for regulating cell division and preventing tumor formation, it has been nicknamed the \"guardian of the genome.\"
", "date_published_by_ghr": "2020-01-07", "conditions_list": [ { "name": "Bladder Cancer", "html_text": "Bladder cancer is a disease in which certain cells in the bladder become abnormal and multiply without control or order. The bladder is a hollow, muscular organ in the lower abdomen that stores urine until it is ready to be excreted from the body. The most common type of bladder cancer begins in cells lining the inside of the bladder and is called transitional cell carcinoma (TCC).
Bladder cancer may cause blood in the urine, pain during urination, frequent urination, or the feeling that one needs to urinate without results. These signs and symptoms are not specific to bladder cancer, however. They also can be caused by noncancerous conditions such as infections.
", "ghr_link": "https://ghr.nlm.nih.gov/condition/bladder-cancer" }, { "name": "Breast Cancer", "html_text": "Breast cancer is a disease in which certain cells in the breast become abnormal and multiply uncontrollably to form a tumor. Although breast cancer is much more common in women, this form of cancer can also develop in men. In both women and men, the most common form of breast cancer begins in cells lining the milk ducts (ductal cancer). In women, cancer can also develop in the glands that produce milk (lobular cancer). Most men have little or no lobular tissue, so lobular cancer in men is very rare.
In its early stages, breast cancer usually does not cause pain and may exhibit no noticeable symptoms. As the cancer progresses, signs and symptoms can include a lump or thickening in or near the breast; a change in the size or shape of the breast; nipple discharge, tenderness, or retraction (turning inward); and skin irritation, dimpling, or scaliness. However, these changes can occur as part of many different conditions. Having one or more of these symptoms does not mean that a person definitely has breast cancer.
In some cases, cancerous tumors can invade surrounding tissue and spread to other parts of the body. If breast cancer spreads, cancerous cells most often appear in the bones, liver, lungs, or brain. Tumors that begin at one site and then spread to other areas of the body are called metastatic cancers.
A small percentage of all breast cancers cluster in families. These cancers are described as hereditary and are associated with inherited gene mutations. Hereditary breast cancers tend to develop earlier in life than noninherited (sporadic) cases, and new (primary) tumors are more likely to develop in both breasts.
", "ghr_link": "https://ghr.nlm.nih.gov/condition/breast-cancer" }, { "name": "Cholangiocarcinoma", "html_text": "Cholangiocarcinoma is a group of cancers that begin in the bile ducts. Bile ducts are branched tubes that connect the liver and gallbladder to the small intestine. They carry bile, which is a fluid that helps the body digest the fats in food. Bile is produced in the liver and stored in the gallbladder before being released in the small intestine after a person eats.
Cholangiocarcinoma is classified by its location in relation to the liver. Intrahepatic cholangiocarcinoma begins in the small bile ducts within the liver. This is the least common form of the disease, accounting for less than 10 percent of all cases. Perihilar cholangiocarcinoma (also known as a Klatskin tumor) begins in an area called the hilum, where two major bile ducts join and leave the liver. It is the most common form of the disease, accounting for more than half of all cases. The remaining cases are classified as distal cholangiocarcinomas, which begin in bile ducts outside the liver. The perihilar and distal forms of the disease, which both occur outside the liver, are sometimes grouped together and called extrahepatic cholangiocarcinoma.
The three types of cholangiocarcinoma do not usually cause any symptoms in their early stages, and this cancer is usually not diagnosed until it has already spread beyond the bile ducts to other tissues. Symptoms often result when bile ducts become blocked by the tumor. The most common symptom is jaundice, which is a yellowing of the skin and the whites of the eyes. Other symptoms can include itching, dark-colored urine, loss of appetite, unintentional weight loss, abdominal pain, and light-colored and greasy stools. These symptoms are described as \"nonspecific\" because they can be features of many different diseases.
Most people who develop cholangiocarcinoma are older than 65. Because this cancer is often not discovered until it has already spread, it can be challenging to treat effectively. Affected individuals can survive for several months to several years after diagnosis.
", "ghr_link": "https://ghr.nlm.nih.gov/condition/cholangiocarcinoma" }, { "name": "Head And Neck Squamous Cell Carcinoma", "html_text": "Squamous cell carcinoma is a cancer that arises from particular cells called squamous cells. Squamous cells are found in the outer layer of skin and in the mucous membranes, which are the moist tissues that line body cavities such as the airways and intestines. Head and neck squamous cell carcinoma (HNSCC) develops in the mucous membranes of the mouth, nose, and throat.
HNSCC is classified by its location: it can occur in the mouth (oral cavity), the middle part of the throat near the mouth (oropharynx), the space behind the nose (nasal cavity and paranasal sinuses), the upper part of the throat near the nasal cavity (nasopharynx), the voicebox (larynx), or the lower part of the throat near the larynx (hypopharynx). Depending on the location, the cancer can cause abnormal patches or open sores (ulcers) in the mouth and throat, unusual bleeding or pain in the mouth, sinus congestion that does not clear, sore throat, earache, pain when swallowing or difficulty swallowing, a hoarse voice, difficulty breathing, or enlarged lymph nodes.
HNSCC can spread (metastasize) to other parts of the body, such as the lymph nodes or lungs. If it spreads, the cancer has a worse prognosis and can be fatal. About half of affected individuals survive more than five years after diagnosis.
", "ghr_link": "https://ghr.nlm.nih.gov/condition/head-and-neck-squamous-cell-carcinoma" }, { "name": "Li-Fraumeni Syndrome", "html_text": "Li-Fraumeni syndrome is a rare disorder that greatly increases the risk of developing several types of cancer, particularly in children and young adults.
The cancers most often associated with Li-Fraumeni syndrome include breast cancer, a form of bone cancer called osteosarcoma, and cancers of soft tissues (such as muscle) called soft tissue sarcomas. Other cancers commonly seen in this syndrome include brain tumors, cancers of blood-forming tissues (leukemias), and a cancer called adrenocortical carcinoma that affects the outer layer of the adrenal glands (small hormone-producing glands on top of each kidney). Several other types of cancer also occur more frequently in people with Li-Fraumeni syndrome.
A very similar condition called Li-Fraumeni-like syndrome shares many of the features of classic Li-Fraumeni syndrome. Both conditions significantly increase the chances of developing multiple cancers beginning in childhood; however, the pattern of specific cancers seen in affected family members is different.
", "ghr_link": "https://ghr.nlm.nih.gov/condition/li-fraumeni-syndrome" }, { "name": "Lung Cancer", "html_text": "Lung cancer is a disease in which certain cells in the lungs become abnormal and multiply uncontrollably to form a tumor. Lung cancer may not cause signs or symptoms in its early stages. Some people with lung cancer have chest pain, frequent coughing, blood in the mucus, breathing problems, trouble swallowing or speaking, loss of appetite and weight loss, fatigue, or swelling in the face or neck. Additional symptoms can develop if the cancer spreads (metastasizes) into other tissues. Lung cancer occurs most often in adults in their sixties or seventies. Most people who develop lung cancer have a history of long-term tobacco smoking; however, the condition can occur in people who have never smoked.
Lung cancer is generally divided into two types, small cell lung cancer and non-small cell lung cancer, based on the size of the affected cells when viewed under a microscope. Non-small cell lung cancer accounts for 85 percent of lung cancer, while small cell lung cancer accounts for the remaining 15 percent.
Small cell lung cancer grows quickly and in more than half of cases the cancer has spread beyond the lung by the time the condition is diagnosed. Small cell lung cancer often metastasizes, most commonly to the liver, brain, bones, and adrenal glands (small hormone-producing glands located on top of each kidney). After diagnosis, most people with small cell lung cancer survive for about 1 year; less than seven percent survive 5 years.
Non-small cell lung cancer is divided into three main subtypes: adenocarcinoma, squamous cell carcinoma, and large cell lung carcinoma. Adenocarcinoma arises from the cells that line the small air sacs (alveoli) located throughout the lungs. Squamous cell carcinoma arises from squamous cells that line the passages leading from the windpipe (trachea) to the lungs (bronchi). Large cell carcinoma arises from epithelial cells that line the lungs. Large cell carcinoma encompasses non-small cell lung cancers that do not appear to be adenocarcinomas or squamous cell carcinomas. The 5-year survival rate for people with non-small cell lung cancer is usually between 11 and 17 percent; it can be lower or higher depending on the subtype and stage of the cancer.
", "ghr_link": "https://ghr.nlm.nih.gov/condition/lung-cancer" }, { "name": "Melanoma", "html_text": "Melanoma is a type of skin cancer that begins in pigment-producing cells called melanocytes. This cancer typically occurs in areas that are only occasionally sun-exposed; tumors are most commonly found on the back in men and on the legs in women. Melanoma usually occurs on the skin (cutaneous melanoma), but in about 5 percent of cases it develops in melanocytes in other tissues, including the eyes (uveal melanoma) or mucous membranes that line the body's cavities, such as the moist lining of the mouth (mucosal melanoma). Melanoma can develop at any age, but it most frequently occurs in people in their fifties to seventies and is becoming more common in teenagers and young adults.
Melanoma may develop from an existing mole or other normal skin growth that becomes cancerous (malignant); however, many melanomas are new growths. Melanomas often have ragged edges and an irregular shape. They can range from a few millimeters to several centimeters across. They can also be a variety of colors: brown, black, red, pink, blue, or white.
Most melanomas affect only the outermost layer of skin (the epidermis). If a melanoma becomes thicker and involves multiple layers of skin, it can spread to other parts of the body (metastasize).
A large number of moles or other pigmented skin growths on the body, generally more than 25, is associated with an increased risk of developing melanoma. Melanoma is also a common feature of genetic syndromes affecting the skin such as xeroderma pigmentosum. Additionally, individuals who have previously had melanoma are nearly nine times more likely than the general population to develop melanoma again. It is estimated that about 90 percent of individuals with melanoma survive at least 5 years after being diagnosed.
", "ghr_link": "https://ghr.nlm.nih.gov/condition/melanoma" }, { "name": "Ovarian Cancer", "html_text": "Ovarian cancer is a disease that affects women. In this form of cancer, certain cells in the ovary become abnormal and multiply uncontrollably to form a tumor. The ovaries are the female reproductive organs in which egg cells are produced. In about 90 percent of cases, ovarian cancer occurs after age 40, and most cases occur after age 60.
The most common form of ovarian cancer begins in epithelial cells, which are the cells that line the surfaces and cavities of the body. These cancers can arise in the epithelial cells on the surface of the ovary. However, researchers suggest that many or even most ovarian cancers begin in epithelial cells on the fringes (fimbriae) at the end of one of the fallopian tubes, and the cancerous cells migrate to the ovary.
Cancer can also begin in epithelial cells that form the lining of the abdomen (the peritoneum). This form of cancer, called primary peritoneal cancer, resembles epithelial ovarian cancer in its origin, symptoms, progression, and treatment. Primary peritoneal cancer often spreads to the ovaries. It can also occur even if the ovaries have been removed. Because cancers that begin in the ovaries, fallopian tubes, and peritoneum are so similar and spread easily from one of these structures to the others, they are often difficult to distinguish. These cancers are so closely related that they are generally considered collectively by experts.
In about 10 percent of cases, ovarian cancer develops not in epithelial cells but in germ cells, which are precursors to egg cells, or in hormone-producing ovarian cells called granulosa cells.
In its early stages, ovarian cancer usually does not cause noticeable symptoms. As the cancer progresses, signs and symptoms can include pain or a feeling of heaviness in the pelvis or lower abdomen, bloating, feeling full quickly when eating, back pain, vaginal bleeding between menstrual periods or after menopause, or changes in urinary or bowel habits. However, these changes can occur as part of many different conditions. Having one or more of these symptoms does not mean that a woman has ovarian cancer.
In some cases, cancerous tumors can invade surrounding tissue and spread to other parts of the body. If ovarian cancer spreads, cancerous tumors most often appear in the abdominal cavity or on the surfaces of nearby organs such as the bladder or colon. Tumors that begin at one site and then spread to other areas of the body are called metastatic cancers.
Some ovarian cancers cluster in families. These cancers are described as hereditary and are associated with inherited gene mutations. Hereditary ovarian cancers tend to develop earlier in life than non-inherited (sporadic) cases.
Because it is often diagnosed at a late stage, ovarian cancer can be difficult to treat; it leads to the deaths of about 14,000 women annually in the United States, more than any other gynecological cancer. However, when it is diagnosed and treated early, the 5-year survival rate is high.
", "ghr_link": "https://ghr.nlm.nih.gov/condition/ovarian-cancer" }, { "name": "Wilms Tumor", "html_text": "Wilms tumor is a form of kidney cancer that primarily develops in children. Nearly all cases of Wilms tumor are diagnosed before the age of 10, with two-thirds being found before age 5.
Wilms tumor is often first noticed because of abdominal swelling or a mass in the kidney that can be felt upon physical examination. Some affected children have abdominal pain, fever, a low number of red blood cells (anemia), blood in the urine (hematuria), or high blood pressure (hypertension). Additional signs of Wilms tumor can include loss of appetite, weight loss, nausea, vomiting, and tiredness (lethargy).
Wilms tumor can develop in one or both kidneys. About 5 to 10 percent of affected individuals develop multiple tumors in one or both kidneys. Wilms tumor may spread from the kidneys to other parts of the body (metastasize). In rare cases, Wilms tumor does not involve the kidneys and occurs instead in the genital tract, bladder, abdomen, chest, or lower back. It is unclear how Wilms tumor develops in these tissues.
With proper treatment, children with Wilms tumor have a 90 percent survival rate. However, the risk that the cancer will come back (recur) is between 15 and 50 percent, depending on traits of the original tumor. Tumors usually recur in the first 2 years following treatment and develop in the kidneys or other tissues, such as the lungs. Individuals who have had Wilms tumor may experience related health problems or late effects of their treatment in adulthood, such as decreased kidney function, heart disease, and development of additional cancers.
", "ghr_link": "https://ghr.nlm.nih.gov/condition/wilms-tumor" } ] } ] }, "genomics_england_panelapp": { "version": "08_jan_2020", "items": [ { "genecolorreview": "Green", "panelid": "243", "genelistname": "Tumour_predisposition_-_childhood_onset.PanelApp.20200108", "genelistotherdata": { "types": [ { "name": "Rare Disease 100K", "description": "Rare Disease 100K" }, { "name": "GMS Rare Disease Virtual", "description": "This is a panel for the Genomic Medicine Service for an exome/genome/panel based test that requires a virtual gene panel for rare disease in the Test Directory." }, { "name": "GMS Cancer Germline Virtual", "description": "This is a panel used for WGS germline analysis for the GMS." }, { "name": "GMS signed-off", "description": "This panel has undergone review by a NHSE GMS disease specialist group and processes to be signed-off for use within the GMS." } ], "currentversion": "2.0", "relevant_disorders": [ { "name": "Paediatric congenital malformation-dysmorphism-tumour syndrome", "id": 18446744073709551615 }, { "name": "Paediatric congenital malformation-dysmorphism-tumour syndromes", "id": 18446744073709551615 }, { "name": "Paediatric congenital malformation-dysmorphism-tumour sydromes", "id": 18446744073709551615 }, { "name": "Paediatric congenital malformation-dysmorphism-tumour syndrome", "id": 18446744073709551615 }, { "name": "R359", "id": 18446744073709551615 } ] }, "genelistdescription": "Tumour syndromes, Childhood Tumours", "levelofconfidence": "3", "penetrance": "Complete", "modeofinheritance": "MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown", "modeofpathogenicity": null, "evidences": [ "NHS GMS", "Expert List", "Expert Review Green", "Eligibility statement prior genetic testing" ], "phenotypes": [ "Adrenocortical carcinoma", "Li Fraumeni Syndrome" ], "pub_med_references": [ 23788249 ] }, { "genecolorreview": "Green", "panelid": "734", "genelistname": "Sarcoma_susceptibility.PanelApp.20200108", "genelistotherdata": { "types": [ { "name": "GMS signed-off", "description": "This panel has undergone review by a NHSE GMS disease specialist group and processes to be signed-off for use within the GMS." }, { "name": "GMS Cancer Germline Virtual", "description": "This is a panel used for WGS germline analysis for the GMS." } ], "currentversion": "1.0", "relevant_disorders": [] }, "genelistdescription": null, "levelofconfidence": "3", "penetrance": null, "modeofinheritance": "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted", "modeofpathogenicity": null, "evidences": [ "Expert Review Green", "NHS GMS" ], "phenotypes": [ "Sarcoma", "Li-Fraumeni syndrome, 151623" ], "pub_med_references": [ 27050224, 28338660 ] }, { "genecolorreview": "Green", "panelid": "217", "genelistname": "Sarcoma_cancer_susceptibility.PanelApp.20200108", "genelistotherdata": { "types": [ { "name": "Cancer Germline 100K", "description": "Cancer Germline 100K" } ], "currentversion": "1.15", "relevant_disorders": [ { "name": "Sarcoma", "id": 30010000004377 }, { "name": "Sarcoma pertinent cancer susceptibility", "id": 18446744073709551615 } ] }, "genelistdescription": "Cancer Programme, Pertinent cancer susceptibility gene panel", "levelofconfidence": "3", "penetrance": "Complete", "modeofinheritance": "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted", "modeofpathogenicity": null, "evidences": [ "Expert Review Green", "Expert list" ], "phenotypes": [ "Sarcoma" ], "pub_med_references": null }, { "genecolorreview": "Green", "panelid": "36", "genelistname": "Multiple_endocrine_tumours.PanelApp.20200108", "genelistotherdata": { "types": [ { "name": "Rare Disease 100K", "description": "Rare Disease 100K" } ], "currentversion": "1.9", "relevant_disorders": [ { "name": "Multiple endocrine tumours", "id": 18446744073709551615 }, { "name": "Multiple endocrine neoplasia type 1", "id": 30010000006607 }, { "name": "Endocrine neoplasia", "id": 18446744073709551615 } ] }, "genelistdescription": "Tumour syndromes, Breast and endocrine", "levelofconfidence": "3", "penetrance": "Complete", "modeofinheritance": "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted", "modeofpathogenicity": null, "evidences": [ "Expert Review Green", "Emory Genetics Laboratory" ], "phenotypes": [ "Endocrine Cancer", "Paragangliomas 1, with or without deafness, 168000", "Pheochromocytoma, 171300", "Carcinoid tumors, intestinal, 114900", "Merkel cell carcinoma, somatic", "Paraganglioma and gastric stromal sarcoma, 606864", "Cowden syndrome 3, 615106" ], "pub_med_references": null }, { "genecolorreview": "Green", "panelid": "525", "genelistname": "Inherited_predisposition_to_acute_myeloid_leukaemia_(AML).PanelApp.20200108", "genelistotherdata": { "types": [ { "name": "GMS Rare Disease", "description": "This panel type is used for GMS panels that are not virtual (i.e. could be a wet lab test)" }, { "name": "GMS signed-off", "description": "This panel has undergone review by a NHSE GMS disease specialist group and processes to be signed-off for use within the GMS." } ], "currentversion": "1.0", "relevant_disorders": [ { "name": "R347", "id": 18446744073709551615 } ] }, "genelistdescription": null, "levelofconfidence": "3", "penetrance": null, "modeofinheritance": "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted", "modeofpathogenicity": null, "evidences": [ "Expert Review Green", "North West GLH", "Yorkshire and North East GLH", "NHS GMS", "Wessex and West Midlands GLH" ], "phenotypes": [ "151623 (OMIM phenotype description ID)", "151623 Li-Fraumeni syndrome" ], "pub_med_references": [ 28600339 ] }, { "genecolorreview": "Red", "panelid": "97", "genelistname": "Inherited_phaeochromocytoma_and_paraganglioma.PanelApp.20200108", "genelistotherdata": { "types": [ { "name": "Rare Disease 100K", "description": "Rare Disease 100K" } ], "currentversion": "1.5", "relevant_disorders": [ { "name": "Neuro-endocrine Tumours- PCC and PGL", "id": 18446744073709551615 } ] }, 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}, "genelistdescription": "Tumour syndromes, Breast and endocrine", "levelofconfidence": "1", "penetrance": "Complete", "modeofinheritance": "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted", "modeofpathogenicity": null, "evidences": [ "Expert Review Red", "Emory Genetics Laboratory", "Expert list", "Radboud University Medical Center, Nijmegen" ], "phenotypes": [ "Colorectal cancer, 114500", "Li-Fraumeni syndrome, 151623", "Hepatocellular carcinoma, 114550", "Osteosarcoma, 259500", "Choroid plexus papilloma, 260500", "Nasopharyngeal carcinoma, 607107", "Pancreatic cancer, 260350", "Adrenal cortical carcinoma, 202300", "Breast cancer, 114480", "{Basal cell carcinoma 7}, 614740", "{Glioma susceptibility 1}, 137800", "High Risk Breast Cancer", "Breast and Ovarian Cancer" ], "pub_med_references": null }, { "genecolorreview": "Green", "panelid": "407", "genelistname": "Haematological_malignancies_for_rare_disease.PanelApp.20200108", "genelistotherdata": { "types": [ { "name": "Rare 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Loss of function mutations (missense, nonsense and frameshift mutations) of TP53 have been described in 10-20% of CLL cases and TP53 gene defects tend to be enriched among cases with unmutated IGH variable regions; in some series, TP53 mutations have been reported in approximately 15%-18% of IGHV unmutated CLL cases . TP53 mutations appears to be less common in other types of CLL (eg, less than 5% of IGHV3-21-expressing CLL carried a TP53 defect according to one study). Mutations of TP53 in CLL have been found together with del17p and mutations in other genes such as NOTCH1 and SF3B1. Mutations and deletions of TP53 appear to represent adverse prognostic markers in chronic lymphocytic leukemia. ", "tissues": [ "Blood", "Bone Marrow", "Lymph Node" ], "tumour_types": [ "Acute Myeloid Leukemia", "Atypical Chronic Myeloid Leukemia", "B Lymphoblastic Leukemia/Lymphoma", "Chronic Myeloid Leukemia", "Chronic Myelomonocytic Leukemia", "Chronic Neutrophilic Leukemia", "Essential Thrombocythemia", "Histiocytic and Dendritic Cell Neoplasms", "Langerhans Cell Histiocytosis", "Mast Cell Neoplasm", "MDS with Ring Sideroblasts", "Myelodysplastic Syndrome", "Myeloproliferative Neoplasm", "Polycythemia Vera", "Primary Myelofibrosis", "T Lymphoblastic Leukemia/Lymphoma", "Leukocytosis", "Thrombocytosis", "Monocytosis", "Cytopenia", "Other Acute Leukemia", "Acute Leukemia of Unspecified Cell Type", "Anemia", "Unspecified", "Leukopenia", "Thrombocytopenia", "Eosinophilia", "Myelodysplastic/Myeloproliferative Neoplasm", "Myeloid Neoplasm", "Polycythemia" ], "disease_or_trait": null, "pub_med_references": [ 23297687, 23334668, 23403321, 24487413, 24619868, 24652989, 24725250, 24943832 ], "variants": [ { "type": "copy number loss", "gene_id": 33956, "definition": "TP53 copy number loss" } ] }, { "tier": 1, "definition": [ "TP53 copy number loss" ], "interpretations": "TP53 is a well known tumor suppressor gene that is mutated in wide variety of cancers. In terms of myeloid disorders, missense, nonsense, and frameshift mutations of TP53 tend to occur in the DNA binding domain and have been reported in approximately 4% of cases of AML where they tend to be associated with a poorer prognosis and an adverse cytogenetic risk profile. TP53 mutations also occur in approximately 10% of patients with myelodysplastic syndrome (MDS) and are often associated with poorer prognosis, adverse cytogenetic profile and deletion of 5q either in isolation or as part of a complex karyotype. ", "tissues": [ "Blood", "Bone Marrow" ], "tumour_types": [ "Acute Myeloid Leukemia", "Myelodysplastic Syndrome" ], "disease_or_trait": null, "pub_med_references": [ 23297687, 23334668, 23403321, 24487413, 24619868, 24652989, 24725250, 24943832 ], "variants": [ { "type": "copy number loss", "gene_id": 33956, "definition": "TP53 copy number loss" } ] }, { "tier": 1, "definition": [ "TP53 copy number loss" ], "interpretations": " TP53 is a well known tumor suppressor gene that is mutated in wide variety of cancers. Among cases of acute lymphoblastic leukemia, overall TP53 mutations are reported to occur in less than 10% of cases. However, TP53 mutations have a very high prevalence (approximately 90%) among cases of ALL with low hypodiploid karyotype and in this setting are often associated with monosomy 17 and may be associated with germline TP53 mutations in a significant proportion of such cases in children. ", "tissues": [ "Blood", "Bone Marrow" ], "tumour_types": [ "B Lymphoblastic Leukemia/Lymphoma" ], "disease_or_trait": null, "pub_med_references": [ 23297687, 23334668, 23403321, 24487413, 24619868 ], "variants": [ { "type": "copy number loss", "gene_id": 33956, "definition": "TP53 copy number loss" } ] }, { "tier": 1, "definition": [ "TP53 any mutation" ], "interpretations": "TP53 encodes p53, a tumor suppressor protein that consists of transactivation domain, proline-rich domain, DNA-binding domain, oligomerization domain, and regulatory domain. p53 responds to diverse cellular stresses to maintain genomic stability and to induce cell cycle arrest, apoptosis, DNA repair and metabolic changes. TP53 mutations represent an important mechanism of resistance to DNA-damaging chemotherapeutic agents. Somatic TP53 mutations are found in a variety of cancers with various frequencies depending on cancer type; overall, TP53 is mutated in over one-half of human cancers. Missense mutations were the most frequent (~70-80%), followed by frameshift and nonsense mutations. Most TP53 mutations are clustered in the DNA-binding domain encompassing exons 5 and 8. These mutations either directly disrupt the DNA-binding domain of TP53 or cause conformational changes of the TP53 protein, thus leading to severely impaired TP53 function. Overall in myeloid malignancies, TP53 mutations are found in 5% to 15% of de novo MDS and AML but 20% of myelodysplastic syndrome with isolated del(5q) and ~50% of MDS/AML with complex karyotype. TP53 mutations are also more frequent in therapy-associated myeloid neoplasm (21-38%) compared to de novo MDS and AML. TP53 mutations are also found in 8% of blastic plasmacytoid dendritic cell neoplasm, and less than 5% in myeloproliferative neoplasms (ET, PV and PMF) and chronic myelomonocytic leukemia. TP53 mutations are independently associated with a poor prognosis in myelodysplastic syndrome (NCCN Guidelines for Myelodysplastic Syndromes) and is a poor risk factor in AML (NCCN Guildelines for AML). TP53 mutations are also associated with resistance to lenalidomide or relapse during lenalidomide treatment. TP53 mutations are independently associated with unfavorable outcomes and shorter survival after hematopoietic stem cell transplantation in patients with myelodysplastic syndrome and myelodysplastic syndrome/acute myeloid leukemia, but an increased response to decitabine in patients with myelodysplastic syndrome or acute myeloid leukemia.\n\n", "tissues": [ "Blood", "Bone Marrow" ], "tumour_types": [ "Acute Myeloid Leukemia", "Atypical Chronic Myeloid Leukemia", "B Lymphoblastic Leukemia/Lymphoma", "Chronic Myeloid Leukemia", "Chronic Myelomonocytic Leukemia", "Chronic Neutrophilic Leukemia", "Essential Thrombocythemia", "Histiocytic and Dendritic Cell Neoplasms", "Langerhans Cell Histiocytosis", "Mast Cell Neoplasm", "MDS with Ring Sideroblasts", "Myelodysplastic Syndrome", "Myeloproliferative Neoplasm", "Polycythemia Vera", "Primary Myelofibrosis", "T Lymphoblastic Leukemia/Lymphoma", "Leukocytosis", "Thrombocytosis", "Monocytosis", "Cytopenia", "Other Acute Leukemia", "Acute Leukemia of Unspecified Cell Type", "Anemia", "Unspecified", "Leukopenia", "Thrombocytopenia", "Eosinophilia", "Myelodysplastic/Myeloproliferative Neoplasm", "Myeloid Neoplasm", "Polycythemia" ], "disease_or_trait": null, "pub_med_references": [ 18596741, 21519010, 21714678, 22052707, 23690417, 24072100, 25952993, 26618142, 27288520, 27463065, 27601546, 27959731, 27967292, 29296692 ], "variants": [ { "type": "any mutation", "gene_id": 33956, "definition": "TP53 any mutation" } ] }, { "tier": 2, "definition": [ "TP53 any mutation" ], "interpretations": "Somatic mutations in TP53 are frequent in human cancer. Germline TP53 mutations cause of Li-Fraumeni syndrome, which is associated with a range of early-onset cancers. The types and positions of TP53 mutations are diverse. TP53 mutations may be potential prognostic and predictive markers in some tumor types, as well as targets for pharmacological intervention in some clinical settings. The IARC TP53 Database (http://www-p53.iarc.fr/) is a useful resource which catalogues TP53 mutations found in cancer.", "tissues": [ "Skin" ], "tumour_types": [ "Melanoma" ], "disease_or_trait": null, "pub_med_references": [ 20182602 ], "variants": [ { "type": "any mutation", "gene_id": 33956, "definition": "TP53 any mutation" } ] }, { "tier": 2, "definition": [ "TP53 any mutation" ], "interpretations": "Somatic mutations in TP53 are frequent in human cancer. Germline TP53 mutations cause of Li-Fraumeni syndrome, which is associated with a range of early-onset cancers. The types and positions of TP53 mutations are diverse. TP53 mutations may be potential prognostic and predictive markers in some tumor types, as well as targets for pharmacological intervention in some clinical settings. The IARC TP53 Database (http://www-p53.iarc.fr/) is a useful resource which catalogues TP53 mutations found in cancer.", "tissues": [ "Appendix", "Colon", "Rectum" ], "tumour_types": [ "Adenocarcinoma" ], "disease_or_trait": null, "pub_med_references": [ 20182602 ], "variants": [ { "type": "any mutation", "gene_id": 33956, "definition": "TP53 any mutation" } ] }, { "tier": 2, "definition": [ "TP53 any mutation" ], "interpretations": "Somatic mutations in TP53 are frequent in human cancer. Germline TP53 mutations cause of Li-Fraumeni syndrome, which is associated with a range of early-onset cancers. The types and positions of TP53 mutations are diverse. TP53 mutations may be potential prognostic and predictive markers in some tumor types, as well as targets for pharmacological intervention in some clinical settings. The IARC TP53 Database (http://www-p53.iarc.fr/) is a useful resource which catalogues TP53 mutations found in cancer.", "tissues": [ "Brain" ], "tumour_types": [ "Glioblastoma" ], "disease_or_trait": null, "pub_med_references": [ 20182602 ], "variants": [ { "type": "any mutation", "gene_id": 33956, "definition": "TP53 any mutation" } ] }, { "tier": 2, "definition": [ "TP53 copy number loss", "TP53 any deletion" ], "interpretations": "P53 activates the transcription of genes involved in cell cycle arrest, DNA repair, and apoptosis. Deletion and point mutation at the TP53 locus occur in 25%-40% and 5%-40% of prostate cancer, respectively. Although the frequency of p53 mutations seems to be lower in prostate cancer than in other cancers, these alterations are not exclusively late events, as they have been shown in 25% to 30% of clinically localized prostate cancer. Several studies indicate that p53 overexpression may be associated with poor prognosis, especially when present in combination with Bcl2. Interestingly, SPOP mutations are also mutually exclusive with deletions and mutations in the TP53 tumor suppressor.\n", "tissues": [ "Prostate" ], "tumour_types": [ "Adenocarcinoma" ], "disease_or_trait": null, "pub_med_references": [ 23759327, 26695660 ], "variants": [ { "type": "copy number loss", "gene_id": 33956, "definition": "TP53 copy number loss" }, { "type": "any mutation", "gene_id": 33956, "definition": "TP53 any deletion", "coding_impact": "deletion" } ] }, { "tier": 2, "definition": [ "TP53 any mutation" ], "interpretations": "Somatic mutations in TP53 are frequent in human cancer. Germline TP53 mutations cause of Li-Fraumeni syndrome, which is associated with a range of early-onset cancers. The types and positions of TP53 mutations are diverse. TP53 mutations may be potential prognostic and predictive markers in some tumor types, as well as targets for pharmacological intervention in some clinical settings. The IARC TP53 Database (http://www-p53.iarc.fr/) is a useful resource which catalogues TP53 mutations found in cancer.", "tissues": [ "Skin" ], "tumour_types": [ "Langerhans Cell Histiocytosis" ], "disease_or_trait": null, "pub_med_references": [ 20182602 ], "variants": [ { "type": "any mutation", "gene_id": 33956, "definition": "TP53 any mutation" } ] }, { "tier": 2, "definition": [ "TP53 any mutation" ], "interpretations": "Somatic mutations in TP53 are frequent in human cancer. Germline TP53 mutations cause of Li-Fraumeni syndrome, which is associated with a range of early-onset cancers. The types and positions of TP53 mutations are diverse. TP53 mutations may be potential prognostic and predictive markers in some tumor types, as well as targets for pharmacological intervention in some clinical settings. The IARC TP53 Database (http://www-p53.iarc.fr/) is a useful resource which catalogues TP53 mutations found in cancer.", "tissues": [ "Adrenal Gland", "Anus", "Ampulla (Pancreaticobiliary Duct)", "Appendix", "Bladder", "Blood", "Bone", "Bone Marrow", "Brain", "Breast", "Spinal Cord", "Cervix", "Chest Wall", "Colon", "Endometrium", "Esophagus", "Eye", "Fallopian Tube", "Fibroadipose Tissue", "Gall Bladder", "Kidney", "Larynx", "Liver", "Lung", "Lymph Node", "Nasal Cavity", "Oral Cavity", "Ovary", "Pancreas", "Parathyroid", "Penis", "Peripheral Nervous System", "Peritoneum", "Pharynx", "Pituitary", "Placenta", "Pleura", "Prostate", "Retroperitoneum", "Salivary Gland", "Seminal Vesicle", "Skeletal Muscle", "Skin", "Small Intestine", "Soft Tissue", "Spleen", "Stomach", "Testis", "Thymus", "Thyroid", "Tonsil", "Ureter", "Uterus", "Vagina", "Rectum", "Cartilage", "Blood Vessel", "Buccal Swab", "Heart", "Trachea", "Salivary Duct", "Spermatic Cord", "Vulva", "Infratentorial", "Supratentorial", "Gastroesophageal Junction", "Sellar", "Suprasellar" ], "tumour_types": [ "Acinar Cell Carcinoma", "Acinic Cell Carcinoma", "Adenocarcinoma", "Adenoid Cystic Carcinoma", "Adenosarcoma", "Ameloblastic Tumor", "Anaplastic Large Cell Lymphoma", "Angioimmunoblastic T-Cell Lymphoma", "Angiomatoid Fibrous Histiocytoma", "Angiomatosis", "Angiomyolipoma", "Angiosarcoma", "Astrocytoma", "Anaplastic", "Basal Cell Carcinoma", "Burkitt Lymphoma", "Carcinoid Tumor", "Carcinoma", "Carcinosarcoma", "Cholangiocarcinoma", "Chondrosarcoma", "Chordoma", "Choriocarcinoma", "Chromophobe Renal Cell Carcinoma", "Chronic Lymphocytic Leukemia", "Classical Hodgkin Lymphoma", "Clear Cell Carcinoma", "Clear Cell Renal Cell Carcinoma", "Craniopharyngioma", "Dermatofibrosarcoma", "Desmoplastic Small Round Cell Tumor", "Diffuse Large B Cell Lymphoma", "Ductal Carcinoma", "Ependymoma", "Ewing Sarcoma", "Fibromatosis", "Follicular Carcinoma", "Follicular Lymphoma", "Gastrointestinal Stromal Tumor", "Germ Cell Tumor", "Giant Cell Tumor", "Glioblastoma", "Glomus Tumor", "Granular Cell Tumor", "Hairy Cell Leukemia", "Hemangioendothelioma", "Hepatocellular Carcinoma", "Invasive Ductal Carcinoma", "Kaposi Sarcoma", "Leiomyoma", "Leiomyosarcoma", "Lipoma", "Liposarcoma", "Lobular Carcinoma", "Lymphoplasmacytic Lymphoma", "Malignant Mullerian Mixed Tumor", "Mantle Cell Lymphoma", "Marginal Zone B Cell Lymphoma", "Medullary Carcinoma", "Medulloblastoma", "Melanoma", "Meningioma", "Merkel Cell Carcinoma", "Mesothelioma", "Mucinous Tumors of Appendix", "Mucinous Tumors of Ovary", "Mucoepidermoid Carcinoma", "Myxofibrosarcoma", "Nasopharyngeal Carcinoma", "Neuroblastoma", "Neuroendocrine Carcinoma", "Neuroendocrine Neoplasm", "NK Cell Lymphoproliferative Disorder", "NLPHL", "Non-Small Cell Lung Carcinoma", "Oligodendroglioma", "Osteosarcoma", "Papillary Carcinoma", "Papillary Renal Cell Carcinoma", "Peripheral T Cell Lymphoma", "Pheochromocytoma", "Plasma Cell Disorder", "Post-Transplant Lymphoproliferative Disorder", "Primitive Neuroectodermal Tumor", "Renal Cell Carcinoma", "Reninoma", "Retinoblastoma", "Rhabdomyosarcoma", "Sarcoma", "Schwannoma", "Serous Carcinoma", "Sex Cord Stromal Tumor", "Small Cell Carcinoma", "Solid Pseudopapillary Tumor of Pancreas", "Spindle Cell Neoplasm", "Squamous Cell Carcinoma", "T Cell Lymphoproliferative Disorder", "T-Cell LGL Leukemia", "Thymic Carcinoma", "Thymoma", "Urothelial Carcinoma", "Tumors of Peripheral Nerves", "Wilms Tumor", "Pilocytic", "Ganglioglioma", "Neuroepithelial Neoplasm", "NOS", "Pleomorphic Carcinoma", "Solitary Fibrous Tumor", "Neuroepithelial neoplasm", "high grade", "Diffusely Infiltrating", "Diffuse Midline Glioma", "Infiltrating Glioma", "Intraductal Papillary Mucinous Neoplasm (IPMN)", "Lymphadenopathy", "Lymphocytosis", "Symptomatic", "Monoclonal Gammopathy", "Mucinous or Serous Cystic Neoplasms of Pancreas", "Mycosis Fungoides", "Unspecified Site", "Pleomorphic Xanthoastrocytoma", "Rash and Other Nonspecific Skin Eruption" ], "disease_or_trait": null, "pub_med_references": [ 20182602 ], "variants": [ { "type": "any mutation", "gene_id": 33956, "definition": "TP53 any mutation" } ] } ] }, "unil_domino": { "version": "04_sep_2019", "lda_score": 2.7493300000000005, "numberdonor_numbersynonymous": 0.0, "phylop_at_5_prime_utr": 0.5294619999999999, "probability_of_ad": 0.999028, "string_combined_score": 8, "string_experimental_score": 3, "string_text_mining_score": 3, "mrna_half_life": 0 } }