PROJECT SUMMARY/ABSTRACT Over 22,000 new cases of ovarian cancer are diagnosed in the United States each year, of whom only 47.6% survive beyond five years. Ovarian is the most fatal of the gynecologic cancers, due to there being few modifiable risk factors, no effective screening tool, a lack of specific symptoms, and a high probability of recurrence. The only preventive guideline for ovarian cancer is for high-risk, pre-menopausal women (BRCA1/2 carriers, or women with a family history of breast and/or ovarian cancer) to consider undergoing a risk-reducing bilateral salpingo-oopherectomy after child bearing is complete. No official guidelines exist for average-risk women. The etiology of the disease is poorly understood, yet, epidemiologic studies have consistently found that events which interrupt ovulation are protective against ovarian cancer risk, leading to the widely known “incessant ovulation” theory. Specifically, parity (higher number of live births), use of oral contraceptives, and lactation are protective against ovarian cancer, while early age at menarche, late age at menopause, infertility, and nulliparity have the opposite effect. However, the mechanisms through which the initiation and frequency of ovulation influence cancer risk are unknown. One possibility is that the chance of acquiring a cancer-causing mutation increases with each ovulatory cycle, due to inflammation during ovulation that alters the microenvironment to promote DNA damage and seeding of cancer cells. Using two well- characterized, large cohorts with deep phenotype, clinical, and genetic data (the United Kingdom Biobank and Breast Cancer Family Registry), we will use a novel lifecourse epidemiologic approach to investigate how an early life event (age at menarche) and long-term exposure (lifetime ovulatory cycles (LOC), a summary measure that may better capture the accumulated exposure to ovulations than reproductive events considered in isolation) relate to ovarian cancer. Specifically, we propose the following aims: 1) to assess whether the effect of early age at menarche on risk of ovarian cancer is mediated by a high lifetime number of ovulations, 2) to evaluate gene-environment interaction between susceptibility genes and lifetime ovulatory cycles in causing ovarian cancer, and 3) to elucidate the role of ovulations in ovarian cancer causation in a special cohort of women at high risk due to a family history of breast and/or ovarian cancer. This will be the first study to evaluate gene-environment interaction using LOC. The proposed training plan leverages my epidemiologic training by adding cancer substantive knowledge and genomic data analysis skills such that I will be equipped to address both the proposed aims and future research in the genetic bases of ovarian cancer. Execution of these specific aims will advance the NCI's mission to understand the role of inherited mutations in combination with lifestyle and environmental factors, here, in a lethal, ...