ABSTRACT Cancer cells acquire genetic and epigenetic alterations that increase fitness and drive progression through multiple steps of tumor evolution. Recent studies have vastly enhanced our understanding of the genetic events in high-grade serous ovarian cancer (HGSOC), - the most prevalent and lethal form of epithelial ovarian cancer. However, we do not have complete understanding of driver epigenetic alterations that are associated with tumor progression in this disease. In HGSOC, somatic mutations - other than those on P53 - remain uncommon and inter-tumor heterogeneity is high suggesting other genetic or epigenetic events may be primary drivers of the disease. Focusing on a highly prevalent copy number gain of 3q26 locus (~70%) that harbors a potent oncogene PRKCI in conjunction with p53 mutations, we have developed a genetically engineered mouse model of HGSOC. We demonstrated that PRKCI is highly oncogenic in serous ovarian cancer and modulates tumor microenvironment via regulation of immune genes. Our preliminary experiment identified several epigenetic proteins as PRKCI interactors including SMARCA5, MLL5, BAZ2B, MAEL and BCOR suggesting that PRKCI may modulate epigenome. Therefore, we hypothesize that PRKCI amplification and TP53 mutations together set-up specific chromatin states that drive tumorigenesis in ovarian cancer. We further suggest that these epigenomic aberrations can provide specific vulnerabilities for targeted therapies. The objective of this proposal is to identify such chromatin states associated with ovarian cancer progression in specific genetic context of PRKCI or 3q26 amplification and P53 mutation, determine their functional nature and determine the role of PRKCI-interacting chromatin regulators. In aim 1, we will determine the chromatin states in PRKCI overexpressing and P53 mutant serous ovarian epithelium from a genetically engineered mouse model as well as human tumors. In aim 2, we will study contributions of SMARCA5 in PRKCI-mediated epigenome reprogramming and cellular phenotypes in ovarian tumorigenesis. Overall, motivated from the concept of precision medicine, our proposal is focused on identifying epigenomic alterations and vulnerabilities in ovarian cancers that harbor PRKCI overexpression or 3q26 amplification and P53 mutation. 1