The TP53 tumor suppressor gene: From molecular biology to clinical investigations

TL;DR

TP53 is the most frequently mutated gene in human cancer, with roughly 50% of malignancies carrying an alteration, and it acts as a context-dependent transcription factor whose loss or mutation promotes therapy resistance and poor survival. This review synthesizes p53 molecular biology, variant heterogeneity, clinical associations, germline syndromes, and therapeutic strategies, while noting that clinical translation remains limited and p53 is still considered largely undruggable.

Key findings

• TP53 alterations occur in an estimated 50% of human cancers; frequency is highly heterogeneous, from a few percent in thyroid cancer to about 30% in breast cancer and nearly 100% in high-grade serous ovarian cancer or small cell lung cancer.
• TP53 mutations are associated with poor response to therapy and shorter survival in most cancer types, with clinical applications established mainly in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML); in mantle cell lymphoma, updated NCCN guidelines recommend TP53 sequencing before treatment.
• p53 regulates cell-cycle arrest, apoptosis, DNA repair, autophagy, senescence, immunity, and the p53-p21 DREAM pathway; mutant p53 may exert dominant-negative and proposed gain-of-function effects, but recent isogenic models challenge gain of function and emphasize loss of function and dominant-negative effects.
• Germline TP53 mutations cause Li-Fraumeni syndrome, and surveillance (Toronto protocol) has been shown to improve survival; the Brazilian founder variant p.R337H is found in 0.3% of the general southern and southeastern Brazilian population. Non-neoplastic phenotypes, including inherited bone marrow failure syndromes and developmental disorders, can arise from chronic p53 activation.

Methods

• Design: narrative review by two authors, covering p53 molecular biology, TP53 mutation heterogeneity, clinical associations, germline mutations, polymorphisms, non-neoplastic syndromes, and therapeutic targeting.
• Data/sample: no primary cohort or systematic search is described; the review cites a literature base including more than 120,000 articles, 13,000 reviews, 500 meta-analyses, sequencing of several hundred thousand tumors, and description of 250,000 mutations, plus TCGA (11,000 cases) and ICGC (25,000 cases) sequencing projects.
• Analysis: thematic synthesis of published mechanistic, structural, murine-model, genomic, and clinical studies, with selected figures summarizing mutation frequency, p53 domains, signaling, and therapeutic strategies.

Limitations

• The authors state the field is too broad to cover fully and refer readers to other reviews for TP53 isoforms, p63/p73, therapeutic strategies, and detailed p53 pathways; they also state that clinical applications of TP53 findings remain restricted to a few cancer types and that p53 is still considered undruggable.
• The authors state that the clinical relevance of the dominant-negative effect remains to be established, that gain-of-function findings have been challenged by more recent isogenic models, and that p53 gene-expression signatures are not currently pertinent for clinic use.
• Evident from the text: as a narrative review, it does not describe a systematic search strategy, inclusion criteria, or formal quality appraisal, so the selection and weighting of cited evidence are author-dependent.