The overall goal of the current proposal is to identify genetic and epigenetic alterations in tubal epithelium from women with BRCA1 mutations that precede development of overt carcinoma. Approximately 10-15% of ovarian carcinomas occur secondary to inherited mutations in BRCA1 and BRCA2, which confer a 20-50% lifetime risk of ovarian carcinoma. This high risk combined with the ineffectiveness of current screening methods has led to the recommendation that women with mutations in BRCA1 and BRCA2 undergo risk-reducing salpingo-oophorectomy (RRSO) by age 40 after completion of child-bearing. A major obstacle in developing improved screening and prevention strategies is the lack of an identifiable premalignant neoplastic lesion that would facilitate study of the early events in malignant transformation. Our group and others have identified a high rate of early carcinomas in the fallopian tubes of BRCA1 mutation carriers undergoing RRSO. We hypothesize that many or most ovarian and peritoneal carcinomas arising in BRCA1 mutation carriers are seeded from malignant cells arising in the fallopian tubes. This phenomenon could have important implications for the screening and prevention of hereditary ovarian carcinoma. We will combine epigenetic analyses with RNA expression studies to find molecular changes in tubal epithelium from BRCA1 mutation carriers that are most likely to be functionally significant. Identification of precursor alterations and proof of their contribution to malignant progression would facilitate chemoprevention trials in high-risk women and provide new targets for early detection.