The etiology of ovarian cancer remains largely unknown, although hormonal factors, inflammation, and wound healing are thought to play important roles. Ovarian cancer is a multifactorial disease and genetic susceptibility has been suggested in previous studies. For example, mutations in BRCA1, BRCA2, MLH1, and MSH2 were found to account for approximately 50% of familial ovarian cancers. However, there are compelling evidence suggesting that common genetic variants contribute to ovarian cancer susceptibility. Recently, genome-wide association studies have identified several common susceptibility alleles in four loci showing strong associations, but as most SNPs identified in GWAs, the associations are usually low in magnitude with most of the ORs less than 1.3. Due to the heterogeneous and multigenic nature of ovarian cancer, it is unlikely that any single SNP will be sufficient to confer disease risk. A comprehensive pathway-based analysis that focuses on evaluating the cumulative effects of a panel of SNPs would be more powerful to pinpoint the susceptibility genes and polymorphisms. The transforming growth factor-b pathway, including TGF-bs, bone morphogenetic proteins, activins, and related proteins, is involved in a diverse array of cellular processes, including cell proliferation, morphogenesis, migration, extracellular matrix production, and apoptosis. Alteration of TGF-b superfamily signaling has been implicated in various human ICG-001 pathologies, including cancer, developmental disorders, cardiovascular and autoimmune diseases. Experimental data have shown that more than 75% of human ovarian cancers exhibit resistance to TGF-b signaling, suggesting that diminished TGF-b responsiveness is a key event in this disease. In normal ovarian surface epithelial cells, autocrine growth inhibition is maintained by TGF-b, but tumor cells escape the antiproliferative effects of TGF-b by acquiring mutations in the components of the signaling pathways or by selectively disrupting TGF-b. Mutations and deletions of Smad genes in the TGF-b signaling pathway often lead to unstable protein products that are rapidly degraded after ubiquitination and shift the equilibrium of the signaling cascade resulting in tumorigenesis. Studies have reported the presence of some common genetic variations in the TGF-b signaling pathway to be related to ovarian carcinogenesis, such as TGFB1: rs56361919 in 23% of ovarian cancer cases. In addition, mutations and/or alterations in the expression of TGF-b receptors and loss of SMAD4 are frequently detected in human ovarian tumors. Given the critical role of the TGF-b pathway in maintaining proper cellular function and the disruption of this pathway in ovarian cancer, it is possible that common genetic variations in this pathway may affect the risk of ovarian cancer. To our knowledge, no molecular epidemiologic studies have been performed to comprehensively evaluate genetic variants in this pathway with ovarian cancer risk. In this study, we aimed to test the hypothesis that common germline genetic variants in the TGF-b pathway are associated with ovarian cancer risk.