Abstract Background Although mutations in TP53 and BRCA1/2 are central to the biology of breast and ovarian cancers, their prognostic roles remain debated, with little attention to tissue-specific differences. Understanding whether the same mutation carries opposite survival implications across cancer types could reshape biomarker interpretation. Methods We interrogated TCGA cohorts of breast cancer ( n = 967) and ovarian cancer (OV; n = 571), defining mutation status by non-synonymous variants. Overall survival was assessed using Kaplan–Meier and multivariable Cox regression models, adjusted for clinical covariates. Complete-case subsets were analyzed for robustness. Results In breast cancer, BRCA2 mutations conferred a strikingly adverse prognosis (HR = 3.91; 95% CI, 1.10–13.9; p = 0.034), while BRCA1 and TP53 showed no clear effects. By contrast, in OV, BRCA2 mutations were linked to markedly improved survival (HR = 0.18; 95% CI, 0.04–0.82; p = 0.018). BRCA1 showed a trend toward benefit, whereas TP53 mutations, though nearly ubiquitous, were not prognostic. Conclusions This work uncovers a paradoxical, tissue-specific divergence in the prognostic value of BRCA2 mutations: detrimental in breast cancer yet favorable in OV. Such opposing effects have not been systematically highlighted before and emphasize the need for cancer-type–tailored biomarker strategies. These results are hypothesis-generating but highlight the translational importance of context in precision oncology.
Parvin Pourmasoumi (Fri,) studied this question.