TP53 – Breast Cancer

Autosomal dominant germline mutations in TP53 confer a high lifetime risk of breast cancer, often in the context of Li-Fraumeni syndrome. Female carriers develop breast cancer at a median age of <35 years and frequently present with bilateral, early-onset, and HER2-positive tumors. These observations support clinical testing for TP53 variants in young breast cancer patients, particularly those with family history or early HER2 positivity.

Genetic evidence includes over 200 unrelated breast cancer probands harboring TP53 variants, spanning missense (e.g., c.742C>T (p.Arg248Trp)), nonsense, splice, and frameshift defects. Familial segregation has been documented in multiple kindreds, with at least seven additional affected relatives carrying the same variant. The recurrent Brazilian founder mutation p.Arg337His accounts for ~8.6% of early-onset breast cancers in unselected Southern cohorts. Variant spectrum: predominantly missense disruptions of the DNA-binding domain, with rare loss-of-function and splice mutants reported across exons 5–8.

Phenotypic correlation shows that 63–83% of breast tumors in TP53 carriers are HER2-positive, compared with 25% in non-carriers (odds ratio 6.9, P=.0001). Germline TP53 variants occur in ~0.5% of unselected breast cancer cases and 3.8% of patients ≤30 years old in large Asian cohorts. TP53 carriers demonstrate poor recurrence-free survival and may benefit preferentially from platinum-based neoadjuvant regimens ([PMID:31119730]; [PMID:23580068]; [PMID:21761402]).

Mechanistically, wild-type p53 activates transcription via sequence-specific DNA binding, inducing cell cycle arrest or apoptosis. Transforming p53 mutants lose transcriptional activation capacity ([PMID:2144364]), adopt aberrant conformations at 37 °C ([PMID:2258922]), and exhibit deficient DNA binding ([PMID:2047879]). In vivo studies show that loss of p53 cooperates with oncogenic PIK3CA to accelerate mammary tumorigenesis, underscoring haploinsufficiency as a key driver ([PMID:21324922]).

Conflicting data include a low prevalence (1.4%) of TP53 mutations in young women with HER2+ tumors and no significant somatic TP53 mosaicism in chemotherapy-exposed blood cells. These findings suggest age, family history, and tumor subtype should guide TP53 testing ([PMID:23580068]; [PMID:26847329]).

In summary, robust genetic and functional evidence supports a Definitive association between germline TP53 mutations and early-onset breast cancer. Routine TP53 testing in young, HER2-positive, or Li-Fraumeni-like breast cancer cases can inform risk management and tailored therapy.

References

• Cancer • 2012 • Early onset HER2-positive breast cancer is associated with germline TP53 mutations PMID:21761402
• Breast Cancer Res Treat • 2013 • Prevalence of germline TP53 mutations in HER2+ breast cancer patients PMID:23580068
• Int J Cancer • 2020 • Prevalence and clinical impact of TP53 germline mutations in Chinese women with breast cancer PMID:31119730
• Science • 1990 • Transcriptional activation by wild-type but not transforming mutants of the p53 anti-oncogene PMID:2144364
• J Mol Biol • 1990 • Temperature-dependent switching between "wild-type" and "mutant" forms of p53-Val135 PMID:2258922
• Science • 1991 • Identification of p53 as a sequence-specific DNA-binding protein PMID:2047879
• Cancer Res • 2011 • Cooperation between Pik3ca and p53 mutations in mouse mammary tumor formation PMID:21324922
• JAMA Oncol • 2016 • Somatic Mosaic Mutations in PPM1D and TP53 in the Blood of Women With Ovarian Carcinoma PMID:26847329

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