TP53

Overview

TP53 (Tumor Protein P53) encodes the p53 transcription factor, the most frequently mutated gene across all human cancers. p53 acts as a master regulator of the DNA damage response, cell cycle arrest, apoptosis, and senescence. TP53 is inactivated by missense mutation (often with dominant-negative gain-of-function effects), deletion, or MDM2-mediated degradation. Its mutation frequency varies substantially by cancer type, and in the metastatic setting TP53 is often enriched relative to primary tumors. Germline TP53 mutations define Li-Fraumeni syndrome.

Alterations observed in the corpus

  • Somatic mutation identified in the TCGA PCC/PGL cohort (pcpg_tcga_pub, n=173) as part of a cancer-relevant gene scan alongside SETD2 and ARNT. PMID:28162975
  • Germline TP53 S215N missense identified in a pediatric AML patient in the PIPseq program (n=101, Columbia University); explained lack of response to conventional therapy and increased other-cancer risk. PMID:28007021
  • Significantly mutated in both EAC and ESCC in the TCGA esophageal carcinoma cohort (stes_tcga_pub, n=164 esophageal); notably mutated in only 1 of 4 ESCC3 tumors. PMID:28052061
  • Mutated in 27% of HR+/HER2− metastatic breast cancer (mBC) vs 20% of HR+/HER2− early breast cancer (eBC) in 216 mBC patients (Fisher p=0.13, not statistically significant); TP53 mutation is not enriched in the metastatic setting for HR+/HER2− subtype. PMID:28027327
  • TP53 recurrently altered at baseline in SCLC PDX models; alterations preserved through acquired cisplatin/etoposide resistance with no evidence of additional acquired TP53 mutations under chemotherapy selection PMID:28196596.
  • TP53 significantly enriched in the unknown mitogenic driver (UMD) subset of 860 metastatic LUAD patients profiled by MSK-IMPACT (p<0.05 vs level 1–4 cohort); elevated in heavy-smoker UMD samples PMID:28336552.
  • Single TP53 R248W missense event observed in an acral lentiginous melanoma (ACRM) cohort of 34 patients; MDM2/TP53 (apoptosis/senescence) pathway altered in 17% of ALM patients PMID:28373299.
  • Driver SNV in lung adenocarcinoma (LUAD); not associated with pre-operative ctDNA detection within LUADs in the TRACERx circulating tumor DNA study PMID:28445469
  • E258K mutation in 1/19 sequenced oligodendroglioma tumors PMID:28472509
  • Most frequently altered gene in pan-cancer MSK-IMPACT analysis (41% of 10,336 samples across 62 tumor types); largely truncating/splice-disrupting inactivating mutations; significantly enriched vs TCGA in prostate (PRAD), chromophobe renal cell carcinoma (CHRCC), glioblastoma, and gastric cancer PMID:28481359
  • Mutated in 39.7% of CCEC; enriched in serous-like CCECs; co-enriched with PPP2R1A mutations in serous-like molecular profiles PMID:28485815
  • Alterations rise stepwise with stage/grade in NMIBC (p<0.001); co-listed with MDM2 as part of the TP53/MDM2 pathway enriched at higher tumor stage and grade PMID:28583311
  • Significantly enriched in CCA Clusters 1 and 2 (p < 0.001); mutation associated with increased structural variant burden (q < 0.1) PMID:28667006
  • Germline variants predominantly restricted to SHH medulloblastoma in the 491-sample ICGC cohort PMID:28726821
  • Most frequently altered tumor suppressor across 500 metastatic solid tumors (266/500, 53.2%); also recurrent in fusions (n=11) as a tumor-suppressor breakage event PMID:28783718
  • Present at 27% locoregional / 30% metastatic noncastrate / 48% mCRPC prostate cancer; clonal early events in matched primaries of patients who progress to metastasis, consistent with aggressive behavior PMID:28825054
  • Recurrent driver in DLBCL; mutually exclusive with KLHL6; CRISPR-enriched (loss of TP53 increases fitness) PMID:28985567
  • Mutated in 48% of MIBC; enriched in basal-squamous and neuronal subtypes; co-occurs with RB1 and E2F3 amplification; mutually exclusive with MDM2 amplification and CDKN2A loss; enriched in genome-doubled tumors (p < 10⁻⁷) PMID:28988769
  • Pan-sarcoma SMG; mutated in 50% of LMS (40/80); deep deletions in 9% LMS, 16% UPS, 12% MFS PMID:29100075
  • Most frequently mutated gene (73%) in metastatic gastric/gastroesophageal junction cancer (HER2-positive cohort); enriched relative to TCGA EGC non-MSI-H (62%) PMID:29122777
  • Mutated in 78% of mCRC cases; the only gene significantly enriched in metastatic vs early-stage colorectal primaries. PMID:29316426
  • Altered in 67% of durable clinical benefit (DCB) and 54% of no-durable-benefit (NDB) NSCLC patients on anti-PD-(L)1 therapy; no significant enrichment for response or non-response. PMID:29337640
  • Co-mutation with HER2 (ERBB2) enriched in patients without clinical benefit to neratinib (nominal p=0.018), associated with cell-cycle pathway co-alterations in pan-tumor HER2-mutant basket trial. PMID:29420467
  • Somatic mutations present in HPV(−) vulvar squamous cell carcinomas; named the most commonly mutated gene in HPV(−) vulvar SCC consistent with prior literature. PMID:29422544
  • Six LP/PV carriers (21.4% of LP/PV carriers) in a pediatric cancer cohort; strongest single-gene burden-test association (OR=32.8, p=7.83x10^-8). Recurrent c.586C>T p.(Arg196*) detected twice. Three of six carriers (50%) developed secondary malignant neoplasms; carriers presented with rhabdomyosarcoma, osteosarcoma, or BCP-ALL PMID:29489754
  • Called as a KIRC SMG by both MutSig2CV and MuSiC2 on the TCGA MC3 open-access MAF; one of the canonical pan-cancer drivers consistently recovered across callers PMID:29596782
  • Confirmed established prostate cancer driver in the SU2C/PCF 1,013-sample cohort; enriched in metastatic vs. primary tumors; part of the metastasis-enrichment genomic marker set proposed for prospective risk stratification PMID:29610475
  • Predominantly mutated (not fused) across cancer types; an exception is SARC where both TP53 fusion and mutation events were observed in the TCGA pan-cancer fusion landscape PMID:29617662
  • The only somatic mutation positively associated with high aneuploidy in the pan-cancer linear model (coefficient +0.13); even with p53 inhibited via SV40 large-T in AALE cells, chr_3p deletion still slowed proliferation initially, suggesting non-TP53 mechanisms also restrain aneuploidy PMID:29622463

Cancer types (linked)

  • PHC / PGNG: Somatic TP53 mutation identified as a cancer-relevant gene scan finding; not a primary driver in this low-mutation-burden tumor type. PMID:28162975
  • AML: Germline TP53 S215N — a functionally relevant mutation explaining conventional-therapy resistance and conferring elevated risk for secondary cancers; family counseling implications. PMID:28007021
  • ESCC / ESCA: TP53 is a significantly mutated gene in both ESCC and EAC; low frequency in ESCC3 distinguishes this subtype. PMID:28052061
  • BRCA: TP53 mutation rate (27%) in HR+/HER2− mBC is slightly above eBC (20%) but not statistically enriched (p=0.13); TP53 is not a metastasis-specific driver in HR+/HER2− breast cancer. PMID:28027327

Co-occurrence and mutual exclusivity

  • In PCC/PGL, somatic TP53 mutation occurred in a context of otherwise mutually exclusive driver events; driver gene mutual exclusivity was significant (p < 1e-4) across the 21-gene set. PMID:28162975
  • In ESCC, TP53 is nearly universally mutated and does not show the same strong mutual exclusivity pattern as in PCC/PGL. PMID:28052061

Therapeutic relevance

  • Germline TP53 S215N in pediatric AML explained poor response to conventional therapy; this finding has implications for altered treatment strategies and second-cancer surveillance. PMID:28007021

Open questions

  • The functional significance of somatic TP53 mutation in PCC/PGL (a tumor type with low overall mutation burden) and its relationship to tumor aggressiveness requires further characterization. PMID:28162975
  • Whether TP53 mutations in metastatic HR+/HER2− breast cancer influence response to CDK4/6 inhibitors or endocrine therapy requires prospective biomarker studies. PMID:28027327

Sources

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This page was processed by wiki-cli on 2026-05-15. - PMID:28783718

This page was processed by wiki-cli on 2026-05-15. - PMID:28825054

This page was processed by wiki-cli on 2026-05-15. - PMID:28985567

This page was processed by wiki-cli on 2026-05-15. - PMID:28988769

This page was processed by wiki-cli on 2026-05-15. - PMID:29100075

This page was processed by wiki-cli on 2026-05-15. - PMID:29122777

This page was processed by wiki-cli on 2026-05-15. - PMID:29316426

This page was processed by wiki-cli on 2026-05-15. - PMID:29337640

This page was processed by wiki-cli on 2026-05-15. - PMID:29420467

This page was processed by wiki-cli on 2026-05-15. - PMID:29422544

This page was processed by entity-page-writer on 2026-05-15. - PMID:29489754

This page was processed by wiki-cli on 2026-05-15. - PMID:29596782

This page was processed by wiki-cli on 2026-05-15. - PMID:29610475

This page was processed by wiki-cli on 2026-05-15. - PMID:29617662

This page was processed by wiki-cli on 2026-05-15. - PMID:29622463

This page was processed by wiki-cli on 2026-05-15.