Hormones, DNA Repair, BRCA1/2 and Ovarian Cancer Preven*

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DESCRIPTION (provided by applicant): Ovarian cancer is an insidious disease and a potent killer. Prevention is currently the best way to reduce morbidity and mortality. Determining etiologic factors and identifying women at an increased risk is the first step in devising an effective prevention program. For women carrying a BRCA1/2 mutation, prevention is even more critical because they are 10 times more likely to develop the disease than women are in general. However, the considerable variability in penetrance and age at onset of BRCA1/2-associated disease suggests the existence of common, modifying factors. Identifying such factors is important because it will enable us to develop strategies for risk assessment and targeted prevention efforts. Sex steroid hormones have been implicated in ovarian cancer; thus, factors that alter the availability of these hormones could impact ovarian cancer risk in general and among BRCA1/2 carriers. Polymorphisms in genes along the sex steroid pathways may be such factors. Evidence is mounting for a role of these polymorphisms in several hormonally-related diseases, such as breast cancer. There is also evidence of a role for these gene variants in ovarian cancer. The emerging role of BRCA1 in DNA repair suggests a link between DNA repair genes polymorphisms and BRCA1/2-associated disease. No study has examined these possibilities. We will undertake a case-control study to determine the effects of these polymorphisms on ovarian cancer risk in general and among BRCA1/2 carriers. We will also determine the degree to which exogenous and endogenous hormonal factors modify the risk associated with these polymorphisms. We will obtain genotype data using banked DNA from 300 Ashkenazi Jewish women with histologically-confirmed invasive epithelial ovarian cancer and 300 healthy Ashkenazi Jewish women frequency matched by 5-year age groups to cases. The women previously participated in an NCI-funded study of the epidemiology of ovarian cancer in Jewish women. Detailed data on gynecologic and reproductive history have already been obtained by the parent study using a standardized in-person interview. DNA was also obtained and used to determine the BRCA1/2 status of study participants. This study will identify the most promising allelic variants among the proposed genes, which we will further investigate in a large, multi-national population-based case-control study. This study will also develop the infrastructure needed to undertake a multi-national study examining genetic and environmental determinants of ovarian cancer. The expertise and data we will collect will promote future innovative research into understanding ovarian cancer.