Ovarian cancer is the leading cause of death from gynecologic cancers. The ten year survival is
less than 30% and has not improved significantly over the last 30 years. We employed next generation sequencing to address three common areas where previous studies have been lacking and insight into disease etiology would help improve survival and treatment of patients with ovarian cancer. Firstly, one of the challenges to improved diagnostic and therapeutic intervention in ovarian cancer has been a limited understanding of the natural history of the disease. It has been proposed that fallopian tube cancers may be precursors of high-grade serous ovarian carcinoma (HGSOC) but evolutionary evidence for this hypothesis has been limited. We performed whole exome sequence and copy number analyses of laser-capture microdissected fallopian tube lesions (p53 signatures, serous tubal intraepithelial carcinomas (STICs), and fallopian tube carcinomas), ovarian cancers, and metastases from nine patients. Secondly, to improve our understanding of ovarian cancer, we performed genome-wide analyses of 45 commonly used ovarian cancer cell lines. Lastly, endometrioid and mucinous ovarian cancers represent nearly a quarter of ovarian cancers and their molecular characteristics and pathologic origins are poorly understood. Whole exome sequencing analyses of HGSOC samples demonstrated that p53 signatures and STICs are precursors of ovarian carcinoma and identified a window of seven years between development of a STIC and initiation of ovarian carcinoma, with metastases following rapidly thereafter. Whole genome sequencing analyses of 45 ovarian cancer cell lines showed dose-response analyses to targeted therapies revealed unique molecular dependencies, including increased sensitivity of tumors with PIK3CA and PPP2R1A alterations to PI3K inhibitor GNE-493, MYC amplifications to PARP inhibitor BMN673, and SMAD3/4 alterations to MEK inhibitor MEK162. Finally, whole exome and genome sequencing analyses on less common ovarian cancer subtypes revealed ovarian and GI mucinous tumors were epigenetically distinct. In contrast, the number of alterations and affected genes in ovarian and uterine endometrioid cancers were not distinguishable, suggesting that these tumors may have a similar tissue of origin. Together these analyses provide insights into the etiology of ovarian cancer, have implications for prevention, early detection and therapeutic intervention of this disease
