Mutated p53 in HGSC—From a Common Mutation to a Target for Therapy

SIMPLE SUMMARY: Ovarian high-grade serous cancer (HGSC), the most common and the deadliest subtype of epithelial ovarian cancer, is characterized by frequent mutations in the TP53 tumor suppressor gene, encoding for the p53 protein in nearly 100% of cases. This makes p53 the focus of many studies trying to understand its role in HGSC. The aim of our review paper is to provide updates on the latest findings related to the role of mutant p53 in HGSC. This includes the clinical outcomes of TP53 mutations in HGSC, upstream regulators and downstream effectors of p53, its function in the earliest stages of HGSC development and in the interplay between the tumor cells and their microenvironment. We summarize with the likelihood of p53 mutants to serve as biomarkers for early diagnosis and as targets for therapy in HGSC. ABSTRACT: Mutations in tumor suppressor gene TP53, encoding for the p53 protein, are the most ubiquitous genetic variation in human ovarian HGSC, the most prevalent and lethal histologic subtype of epithelial ovarian cancer (EOC). The majority of TP53 mutations are missense mutations, leading to loss of tumor suppressive function of p53 and gain of new oncogenic functions. This review presents the clinical relevance of TP53 mutations in HGSC, elaborating on several recently identified upstream regulators of mutant p53 that control its expression and downstream target genes that mediate its roles in the disease. TP53 mutations are the earliest genetic alterations during HGSC pathogenesis, and we summarize current information related to p53 function in the pathogenesis of HGSC. The role of p53 is cell autonomous, and in the interaction between cancer cells and its microenvironment. We discuss the reduction in p53 expression levels in tumor associated fibroblasts that promotes cancer progression, and the role of mutated p53 in the interaction between the tumor and its microenvironment. Lastly, we discuss the potential of TP53 mutations to serve as diagnostic biomarkers and detail some more advanced efforts to use mutated p53 as a therapeutic target in HGSC.