Significance of distinct specifically enriched missense TP53 mutations in prostate cancer.

377 Background: The most common TP53 alterations are missense mutations occurring in the DNA binding domain. The majority of missense p53 mutants (mut-p53) demonstrate oncogenic gain-of-function (GOF) abilities, irrespective of wild-type p53 presence, and thus contribute to a more aggressive disease. In prostate cancer (PCa), characterized by comparatively low overall mutational burden, TP53 is frequently mutated in both primary and advanced disease. Despite significant progress made in the field, detailed mechanisms of GOF in PCa remain undefined due to differing features of p53 mutants. Methods: Analysis of available datasets was performed to assess TP53 mutational status in PCa patient samples and its correlation with the clinical outcome. Using hormone therapy sensitive and CRPC cells, a panel of cell lines was generated to model the two most frequently occurring mutations in the presence or absence of wild-type TP53, as occurs clinically. CHIP-seq, gene expression arrays, and in vitro and in vivo biological assays were performed to interrogate the significance of mut-p53 in PCa. Results: In PCa, missense mutations are significantly associated with decreased progression-free and overall survival. In PCa patient samples these mutations most commonly occur at the R273 residue, demonstrating specific enrichment when compared to other cancers, with R273C alteration being the most frequent. Using our cell panel, CHIP-seq data revealed an expansion of the p53 cistrome upon expression of R273C and R273H mutants in a manner distinct from p53 stabilization in the presence of wt-p53. Moreover, analysis of the TP53 missense mutant-sensitive transcriptomes demonstrated differential gene expression between these mutants, related to the expression of wild-type TP53 in those cells. Finally, R273C and R273H p53 mutants elicited context dependent effects on canonical p53 functions, thereby modulating distinct downstream biological outcomes. Conclusions: These data expand our knowledge of the underlying mechanisms by which distinct gain-of-function p53 mutants affect prostate cancer, and can lead to identification of novel therapeutic targets to improve clinical outcomes in PCa patients harboring these mutations.