High grade serous ovarian cancer (HGSOC) is the most common and aggressive form of ovarian cancer. While treatable if detected early, more than 75% of tumors are diagnosed once they have already spread past the ovaries (stage III/IV), resulting in a 5 year survival rate of less than 30%. A lack of adequate screening methods and a high recurrence rate mean that this discouraging prognosis has not improved in the past 30 years. Recent studies have provided compelling evidence that the fallopian tube secretory cell (FTSEC) is the cell of origin for HGSOC. Early precursors containing mutated TP53 have been found in the fallopian tube fimbria, but the environmental factors which contribute to pathogenesis remain poorly understood. Ovulation has long been implicated as an epidemiological risk factor for HGSOC, leading to the incessant ovulation hypothesis which proposes that the constant wounding and healing induced by ovulation leads to increased levels of DNA damage. Understanding how environmental factors can influence HGSOC risk at the molecular level is crucial for the development of early screening techniques. With that goal, this proposal seeks to: 1) treat fallopian tube ex-vivo cultures with follicular fluid and characterize he impact of follicular fluid on DNA damage and repair, as well as global cellular response, 2) to explore the role of reactive oxygen species and other factors in fallopian tube response to follicular fluid, and 3) to determine the interaction between follicular fluid and early precursor lesions by identifying TP53 mutations of interest which are enriched for in P53 precursor or the Cancer Genome Atlas HGSOC datasets, and determining if immortalized FTSEC cells with the mutations of interest present different phenotypes when treated with follicular fluid. Illuminating the early stages of pathogenesis in this deadly disease will provide a solid foundation for the development of early detection techniques and new biomarkers.
Ovarian cancer is a particularly deadly disease because it is typically detected after it has already spread beyond the ovaries, rendering current surgical and drug therapies less effective. This study will investigate the biochemical and molecular mechanisms underlying known epidemiological risk factors for ovarian cancer. Developing a comprehensive understanding of the initial steps in ovarian cancer pathogenesis is germane to establishing early detection techniques and improving survival rates.