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TP53 is the 'guardian of the genome', broken in half of all cancers. Fixing it directly has so far defeated every attempt, so drugs exploit what its loss makes cancers depend on.
TP53 is the most commonly mutated gene in cancer (~50% overall, ~80% in TNBC and ovarian). Direct reactivators (eprenetapopt/APR-246) failed in phase 3; Y220C-specific correctors (rezatapopt) are in registrational trials. Indirect strategies exploit G2/M checkpoint dependence (WEE1, ATR, PLK1) and MDM2 inhibition in TP53-wild-type tumours.
In plain words · TP53 is the 'guardian of the genome', broken in half of all cancers. Fixing it directly has so far defeated every attempt, so drugs exploit what its loss makes cancers depend on.
TP53 is the 'guardian of the genome', broken in half of all cancers. Fixing it directly has so far defeated every attempt, so drugs exploit what its loss makes cancers depend on.
Transcription factor coordinating cell-cycle arrest, apoptosis, and senescence after DNA damage.
4 products aim at TP53: vaccines and small molecules. Because the protein is lost rather than overactive, drugs either restore its function or exploit the weakness its loss leaves (synthetic lethality).
Tumour-specific alteration: 1 of 1 label readouts filed under it measure a sequence variant (TP53 mutation and del(17p)) absent from normal cells. HPA TP53: RNA low tissue specificity; no normal tissue stained high; highest cancer staining ovarian cancer (6 of 12 high). Distribution: 7 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Breast cancer (all types), Ovarian cancer, Lung cancer (all types), Leukaemia, Biliary tract cancer (all types), Pancreatic ductal adenocarcinoma, Colorectal cancer); approvals of single-target medicines aimed at it also list Endometrial cancer, Multiple myeloma, Lymphoma, not counted; Open Targets associates it with 72 specific cancer types at or above 0.5 (Li-Fraumeni syndrome, hepatocellular carcinoma, head and neck squamous cell carcinoma, choroid plexus papilloma, colorectal cancer, basal cell carcinoma, susceptibility to, 7 and more). (Rule 3 of scripts/fetch-target-specificity.ts.)
Sources: TP53 mutation and del(17p); Human Protein Atlas TP53 tissue; Open Targets ENSG00000141510 associations
First described 1984. Earliest sequence paper UniProt cites for the protein: Matlashewski et al, EMBO J, 1984, "Isolation and characterization of a human p53 cDNA clone: expression of the human p53 gene". Source.
What a pathology or genomic report can say about this target, each with the thresholds approvals use.
Cell lines and mouse models for this target →
Transcription factor coordinating cell-cycle arrest, apoptosis, and senescence after DNA damage.
RNA: low tissue specificity, detected in all normal tissues.
No normal tissue stained high; medium in Colon, Esophagus, Oral mucosa, Placenta, Rectum, Testis.
Medium only: melanoma.
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Ovarian cancer | 95% | TP53 mutation (high-grade serous) | cBioPortal (TCGA) | |
| Small-cell lung cancer | >90% | TP53 mutation | RB1 co-loss | Wikipedia |
| Small-cell lung cancer | 86-100% | Biallelic inactivation | cBioPortal: 103 of 120, 85.8%, carry a non-synonymous TP53 mutation in sclc_ucologne_2015. Whole-genome sequencing of 110 small-cell lung cancers found biallelic inactivation of TP53 in nearly all tumours, sometimes through complex genomic rearrangement rather than point mutation, which is why a mutation call alone reads lower (George 2015). | cBioPortal (TCGA) |
| Non-small-cell lung cancer | 83-94% | Mutation | cBioPortal: 404 of 484, 83.5%, in lusc_tcga_pan_can_atlas_2018; 149 of 178, 83.7%, in lusc_tcga_pub; 102 of 108, 94.4%, in lusc_cptac_2021. The founding paper reported mutation of TP53 in nearly all specimens, alongside a mean of 360 exonic mutations, 165 genomic rearrangements and 323 segments of copy-number change per tumour (Cancer Genome Atlas Research Network 2012). | cBioPortal (TCGA) |
| Triple-negative breast cancer | 80-85% | TP53 mutation (basal-like) | cBioPortal (TCGA) | |
| Triple-negative breast cancer | 80% | Mutation | 80% of basal-like tumours in the TCGA breast study (Cancer Genome Atlas 2012); 81% of 447 sequenced TNBCs from METABRIC and TCGA, 92% in the BL1 subtype (Bareche 2018); cBioPortal: 67 of 84 exome-sequenced triple-negative samples, 79.8%, in brca_tcga_pub and 100 of 123, 81.3%, on the 2018 calls; 237 of 299, 79.3%, in brca_metabric; 159 of 176 samples, 90.3%, in breast_msk_2018. TP53, PIK3CA and PTEN mutations were the clonally dominant events in 104 primary TNBCs (Shah 2012). | doi.org |
| Pancreatic ductal adenocarcinoma | 70-75% | TP53 mutation | cBioPortal (TCGA) | |
| Pancreatic ductal adenocarcinoma | 66-76% | Mutation | cBioPortal: 1,778 of 2,336, 76.1%, in pdac_msk_2024; 286 of 395, 72.4%, in pancreas_msk_2024; 105 of 140, 75.0%, in paad_cptac_2021; 253 of 383, 66.1%, in paad_qcmg_uq_2016; 55 of 109, 50.5%, in paad_utsw_2015; 107 of 179, 59.8%, in paad_tcga_pan_can_atlas_2018; 33 of 99 in paad_icgc on 2012 exome depth. Hotspots R175H, R248Q, R248W, R273H and R273C recur. 44.5% of KRAS wild-type tumours (Philip 2022); the squamous subtype is enriched for TP53 and KDM6A mutation (Bailey 2016). | cBioPortal (TCGA) |
| Gallbladder cancer | 63% | Mutation | 63% of 244 MSK-IMPACT samples (Giraldo 2022; cBioPortal gbc_mskcc_2022 counts 154 of 244 sequenced samples, 63.1%); 59% of 85 gallbladder carcinomas on FoundationOne (Javle 2016); 54% of 376 Indian patients (Suryavanshi 2025); 47.1% of 57 Chinese tumour-normal pairs (Li 2014); 30% of 56 Chilean tumours on the Oncomine Comprehensive Assay (Erices 2025); the most mutated gene in 190 patients (Nepal 2021). | doi.org |
| Colorectal cancer | 52-73% | Mutation (with 17p loss) | cBioPortal: 5,295 of 7,237, 73.2%, in crc_msk_2026; 824 of 1,134, 72.7%, in crc_msk_2017; 1,107 of 1,516, 73.0%, in crc_eo_2020; 314 of 534, 58.8%, in coadread_tcga_pan_can_atlas_2018; 121 of 224, 54.0%, in coadread_tcga_pub; 320 of 619, 51.7%, in coadread_dfci_2016. Loss of chromosome 17p sequences was found in 75% of carcinomas but only rarely in early adenomas in the 172 specimens that built the genetic model (Vogelstein 1988). | cBioPortal (TCGA) |
| Colorectal cancer | 55-60% | TP53 mutation | cBioPortal (TCGA) | |
| Non-small-cell lung cancer | 46-54% | Mutation | cBioPortal: 1,429 of 2,653, 53.9%, in luad_mskcc_2023_met_organotropism; 485 of 915, 53.0%, in lung_msk_2017; 295 of 566, 52.1%, in luad_tcga_pan_can_atlas_2018; 107 of 230, 46.5%, in luad_tcga_pub; 59 of 110, 53.6%, in luad_cptac_2020; 109 of 302, 36.1%, in luad_oncosg_2020; 36 of 232, 15.5%, in lung_nci_2022. | cBioPortal (TCGA) |
| Prostate cancer | 3-41% | Inactivating mutation, with deep deletion on top | cBioPortal mutation: 16 of 477, 3.4%, in prad_cpcg_2017 and 26 of 313, 8.3%, in prostate_dkfz_2018, both localised whole-genome cohorts; 57 of 494, 11.5%, in prad_tcga_pan_can_atlas_2018; 189 of 1,013, 18.7%, in prad_p1000; 129 of 424, 30.4%, in prad_mcspc_mskcc_2020; 650 of 2,260, 28.8%, in prostate_msk_2024; 163 of 444, 36.7%, in prad_su2c_2019; 58 of 150, 38.7%, in prad_su2c_2015; 57 of 141, 40.4%, in prad_fhcrc; 25 of 61, 41.0%, in prad_mich. Deep deletion adds 2 to 15% depending on cohort. | cBioPortal (TCGA) |
| Acute myeloid leukaemia | 8-10% | TP53 mutation | Higher in therapy-related AML | cBioPortal (TCGA) |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Eprenetapopt (APR-246) was a drug meant to refold mutant p53, the most common broken protein in cancer. Its phase 3 in blood cancer failed in 2020.
KRT-232 is an experimental small-molecule drug from Kartos Therapeutics in phase 2 trials for myeloproliferative neoplasms, diffuse large B-cell lymphoma and chronic lymphocytic leukaemia, aimed at MDM2 and TP53.
OSE2101 is an experimental cancer vaccine from OSE Immunotherapeutics in phase 3 trials for non-small-cell lung cancer, aimed at HER2 and CEACAM5.
Selinexor is a first-in-class pill that traps tumour-suppressor proteins inside the nucleus; approved in myeloma, it failed its endometrial cancer test in 2026.
The 48 most recent of 75 papers; see them all →
Targeted therapy prevalence estimates from one country may not hold in another, so a UK cohort, with its own ancestry mix, would need its own molecular survey before assuming HER2 or other rates from Asian or Latin American series.
HER2 is as frequent in India as in the West, so HER2 testing pays off in the highest-incidence population, while tumour-agnostic immunotherapy markers will rarely apply. The paper also shows plasma testing is feasible where tissue is scarce.
Evidence that the immune environment of gallbladder cancer differs by population even when the mutations do not; a reason to report gallbladder cancer and its regions separately in immunotherapy trials rather than as one biliary subgroup.
Chile has the world's highest gallbladder cancer mortality and until this paper almost no tumour genomics; the lower TP53 rate and high TSC2 and NOTCH1 hint at a different mutational grammar, but the panel and sample size mean the figures need replication.
The reference Western cohort for gallbladder cancer frequencies, deposited on cBioPortal as gbc_mskcc_2022, where the per-gene sample counts on OnCo were read. It supports panel testing at diagnosis: one patient in three has a targetable finding.
It separates two explanations that are usually run together. Some of the difference in prostate cancer outcomes by race is in the tumour genome and persists when access to the same centre is held constant, and some of it tracks with income rather than with ancestry, so equalising access alone would not eliminate the gap.
This is the fusion and immune-marker table for the wild-type minority, the group in which RNA sequencing pays for itself.
Lung cancer in never-smokers is not smokers' lung cancer with the smoking removed; it is a different set of diseases with a different clock. The slow-growing piano subtype in particular is the argument that a screening test aimed at never-smokers would need to look for something other than what low-dose computed tomography was built to find.
Query for this target: (TITLE:"TP53" OR ABSTRACT:"TP53") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about TP53, not a curated reading list.
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