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Loss of the p53 'guardian of the genome', the most commonly mutated gene in cancer. In blood cancers and several solid tumours a TP53 mutation marks the highest-risk group, resistant to chemotherapy and hard to treat.
TP53 is mutated in about half of all cancers and in almost all high-grade serous ovarian and small-cell lung cancers. Where it is variable it defines risk: TP53-mutated AML and MDS (especially multi-hit) have median survivals under a year and are excluded from many trials; del(17p)/TP53 CLL is treated with BTK inhibitors rather than chemoimmunotherapy; p53-abnormal endometrial cancer (by immunohistochemistry) is the aggressive molecular class that benefits from chemotherapy and trastuzumab if HER2-positive; TP53 and RB1 co-loss in prostate and lung adenocarcinoma predicts neuroendocrine transformation. Restoring p53 (eprenetapopt, MDM2 inhibitors for wild-type tumours) has so far disappointed.
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.
Showing the target this term concerns: TP53.
The glossary entry explains the word; the readout page carries the scoring rule, the thresholds approvals use, the companion diagnostics and the tests.
This paper is the reason TP53 status, MDM2 amplification and CDKN2A loss are read together in tumour genomes. It frames the current drug development around MDM2 inhibitors and mutant p53 reactivators as attempts to restore a network rather than a single protein.
This review fixed the picture of p53 as the guardian of the genome that every textbook uses. It explains why TP53-mutant cancers are aggressive and hard to treat, why MDM2 inhibitors are being developed to reactivate wild-type p53, and why germline TP53 testing matters in families.
This paper is why TP53 status is reported in almost every tumour genome and why mutational signatures can point to causes. Its idea that mutation patterns record exposures grew into the mutational signature field, and TP53 mutation remains a marker of shorter survival and a drug target still being pursued.
Shares Levine 1997: p53, the cellular gatekeeper for growth and division, Vogelstein, Lane and Levine 2000: surfing the p53 network, Li-Fraumeni syndrome (germline TP53), MDM2.
Shares MIPI (Mantle Cell Lymphoma International Prognostic Index), TP53 mutation and del(17p), Cytogenetics and karyotype, Plasma cell leukaemia.
Shares Vogelstein, Lane and Levine 2000: surfing the p53 network, Secondary and therapy-related acute myeloid leukaemia, TP53, Acute myeloid leukaemia.
Shares AML with myelodysplasia-related gene mutations (AML-MR), IPSS-R and IPSS-M (myelodysplastic syndrome risk scores), Secondary and therapy-related acute myeloid leukaemia, Chronic lymphocytic leukaemia.
Shares TP53 mutation and del(17p), Richter transformation of chronic lymphocytic leukaemia, Chronic lymphocytic leukaemia, first treatment, TP53.
Shares No specific molecular profile (NSMP) endometrial cancer, POLE ultramutation (POLEmut), TP53, Endometrial cancer.
Shares IPSS-R and IPSS-M (myelodysplastic syndrome risk scores), Secondary and therapy-related acute myeloid leukaemia, Higher-risk myelodysplastic syndromes, Acute myeloid leukaemia.
Shares Hollstein 1991: p53 mutations in human cancers, Levine 1997: p53, the cellular gatekeeper for growth and division, Vogelstein, Lane and Levine 2000: surfing the p53 network, TP53.