Defining a Pre-Malignant Phenotype in Fallopian Tube Epithelium

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DESCRIPTION (provided by applicant): The lack of an identifiable precursor lesion for ovarian carcinoma hinders attempts to design rational surveillance and chemoprevention for this deadly disease. Indeed, it is uncertain which are the specific cells in the female genital tract that transform into ovarian and primary peritoneal malignancies. A better understanding of the early steps in ovarian tumorigenesis would facilitate the development of new screening and prevention strategies. Inherited mutations in the BRCA1 gene result in an approximate 40% lifetime risk of ovarian, tubal or peritoneal carcinoma. Current clinical recommendations for women with BRCA1 mutations include risk-reducing salpingo-oophorectomy (RRSO) by age 40 after completion of child-bearing. Our group and others have identified a high rate of high-grade serous neoplasia in the fallopian tubes of BRCA1 mutation carriers undergoing RRSO. The frequency of occult tubal neoplasia exceeds that of ovarian neoplasia when using a detailed surgical and pathological protocol. We hypothesize that most ovarian and peritoneal carcinomas arising in BRCA1 mutation carriers are seeded from neoplastic cells arising in the fallopian tubes. This phenomenon could have important implications for the development of sporadic as well as hereditary ovarian carcinoma. The overall goal of the current proposal is to define a premalignant tubal phenotype in women with inherited BRCA1 mutations. The specific aims of this proposal are: 1. Characterize tubal epithelium in unaffected women with BRCA1 mutations and in women with BRCA1- associated or sporadic ovarian and peritoneal carcinomas. 2. Identify and characterize a gene expression signature associated with premalignant alterations in pathologically normal tubal epithelium from women with BRCA1 mutations. 3. Evaluate priority genes from Specific Aim 2 in inherited and sporadic ovarian and peritoneal carcinomas. PUBLIC HEALTH RELEVANCE: An improved understanding of the early steps in ovarian carcinoma development is needed to facilitate rational and novel strategies for screening and prevention. Identification of a pre-cursor lesion for ovarian and peritoneal carcinoma and proof of its potential for malignant progression would facilitate chemoprevention trials in high-risk women and provide new targets for early detection.