We propose to conduct a genome-wide association study to identify loci involved in endometrial cancer causation. We plan to utilize studies with available biospecimens, 6 cohorts from the NCI Cohort Consortium and 7 case-control studies, within the NCI Epidemiology of Endometrial Cancer Consortium, by far the largest international collaborative study of this cancer, the 4th most common in the U.S. Given the large sample size of the combined studies of whites and nonwhites, the best scientific approach to study the role of genetic variants is to pool existing studies of endometrial cancer. To this end we are proposing to conduct the initial genome- wide scan in 2,307 white cases of European descent and 2,307 matched controls using the Illumina HumanHap 610K platform. After the initial scan, we plan to genotype approximately 7,000 markers showing the strongest evidence for association with risk of endometrial cancer in a multiethnic replication sample of 3,258 cases and 3,258 matched controls. The large overall sample size and the large number of markers to be genotyped in the replication samples ensures that we will have very good power to detect the modest marginal genetic effects expected for complex diseases. We will have over 80 percent power in whites (at the genome-wide significance level of 1W10-7) to detect multiplicative odds ratios between 1.19 and 1.30 for risk allele frequencies between 10 percent and 40 percent. In the third characterization stage, we will genotype approximately 60 SNPs in those regions that achieve genome-wide significance in an additional multiethnic sample of 874 cases and 874 controls. Our sample size will also give us the unique opportunity to evaluate effect modification by known risk factors (e.g. body mass index, postmenopausal hormone use, oral contraceptive use) and assess heterogeneity in risk across ethnicity. PUBLIC HEALTH RELEVANCE: Project Narrative Endometrial cancer, the most common gynecological malignancy in the United States, has both an environmental and genetic component. To this end, we propose to conduct a genome-wide association study to identify genes involved in endometrial cancer. We plan to utilize existing studies;they include 6 cohort and 7 case control with a total sample size of 6,439 cases and 6,439 matched controls through 2007. The overall goal is to determine whether certain genotypes are predictive of future endometrial cancer risk, and whether the genotypes interact with established endometrial risk factors.