Dr. Pal's epidemiology-based cancer genetics research has two foci: identification of individuals with genetic and environmental risk factors that place them at increased risk of developing cancer, and development of strategies to reduce this risk. Her currently active research includes studies on ovarian cancer and mismatch repair deficiency and on genetic and hormonal risk factors for breast cancer in African American women. One of the best defined molecular pathways involved in both inherited and sporadic cancer pathogenesis involves the mismatch repair (MMR) pathway, which leads to microsatellite instability (MSI). MSI may result from both genetic (i.e.: germline mutations in the MMR genes, including MLH1, MSH2, and MSH6) and epigenetic (i.e.: MLH1 promoter hypermethylation) mechanisms. The purpose of the ‘Ovarian Cancer and Mismatch Repair Deficiency’ study is to quantify the proportion of ovarian tumors due to the mismatch repair genes and to characterize the tumors in this group. Our ability to classify ovarian cancers by their genetic basis offers promise for improvements in cancer prevention and screening of high risk women, in basing diagnosis and prognosis on molecular markers, and in development of individualized treatments. This study will include 2200 population-based cases of incident epithelial ovarian cancers based at the Moffitt Cancer Center, Duke Comprehensive Cancer Center, and the University of Toronto. Paraffin-embedded tumor samples will be analyzed from all subjects with incident ovarian cancers to perform MSI testing and investigate MMR gene protein expression. In those samples with MSI-H status or with loss of expression of MMR gene proteins, epigenetic (MLH1 promoter hypermethylation) and genetic (germline MMR mutations) will be investigated. Although African American women have a lower overall incidence of breast cancer than Caucasian women, the incidence of early-onset breast cancer is actually higher in African Americans. There is strong evidence that breast cancer in premenopausal women has a significant genetic component. In some cases, the genetic component may be attributable to high-penetrance genes such as BRCA1 and BRCA2; in others, to lower penetrance genes. Most of the low-penetrance genes thus far implicated in increased breast cancer risk are involved in hormone metabolism. Dr. Pal is investigating the contribution of high-penetrance BRCA1/BRCA2 genes in young African American breast cancer patients with a personal or family history suggestive of hereditary predisposition. This study will improve our understanding of inherited breast cancer in young African American women.