Prostatic adenocarcinoma (PCa) remains the second leading cause of cancer death in men in the United States. While organ-confined disease can be successfully treated with surgery or radiation, patients with advanced disease undergo androgen deprivation therapy (ADT), which targets the androgen receptor (AR) signaling axis. This approach effectively treats the disease as PCa cells are exquisitely dependent on AR signaling for proliferation and survival. Unfortunately, cancer progression resumes after 2-3 years and results in a lethal stage of disease, termed castration-resistant prostate cancer (CRPC). While PCa typically demonstrates low overall mutational burden, TP53 is frequently mutated in both primary and advanced disease. These mutations are most commonly missense mutations in the DNA binding domain of TP53, and can occur in the presence or absence of a wildtype TP53 allele. Interestingly, specific enrichment of certain TP53 mutations frequently occurs in PCa when compared to other cancers, and similar to many other cancers, these mutations occur in the presence or absence of wildtype TP53. Using hormone therapy sensitive and CRPC cells, a panel of cell lines was generated to model these mutations in the presence or absence of wildtype TP53 expression. Defining the TP53 missense mutant-sensitive transcriptomes demonstrated context dependent, differential gene expression between TP53 missense mutants, related to the expression of wildtype TP53 in those cells. This also applied to cistrome analysis, illustrating an expansion of the p53 cistrome upon expression of mutant TP53. Furthermore, expression of p53 mutants also elicited context dependent effects on canonical p53 functions, thereby modulating distinct, downstream biological outcomes. Consequently, these data define the distinct and context dependent roles that mutant TP53 plays in PCa progression.

Citation Format: Jennifer J. McCann, Irina Vasilevskaya, Neermala PoudelNeupane, Jeffry Dean, Amy Mandigo, Renee De Leeuw, Chris McNair, Matthew Schiewer, Karen Knudsen. Prostate cancer-specific enrichment of TP53 missense mutations elicits differential, context-dependent biochemical and biologic outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4511.