We propose to continue follow-up of the NCI Breast &Prostate Cancer Cohort Consortium (the BPC3). This Consortium has been established over the last 4 years, and is nearing completion of the assessment of >70 candidate genes in the Steroid Hormone Metabolism and IGF pathways with respect to risk of breast and prostate cancer. Resequencing and genotyping data on these candidate genes was obtained, and tag-SNPs selected for genotyping;these data are available to the research community on a public website. Genotyping in over 7,000 cases of breast cancer, and over 8,500 cases of prostate cancer has been completed or is nearing completion. With the accrual of additional cases by mid-2007, we expect that these databases can be expanded to 14,000 cases and controls of breast cancer, and 16,000 cases and controls of prostate cancer. Starting in 2005, the NCI Cancer - Genetic Markers of Susceptibility (CGEMS) project, has been conducting genome-wide SNP scans in two of the BPC3 studies (prostate cancer in the PLCO study, and breast cancer in the Nurses'Health Study) with replication forSNPs highly ranked in the scan in the other studies of the BPC3. Other genome-wide association studies are ongoing, including an admixture scan for prostate cancer in the MEC, a breast cancer scan using pooled DNAs in the Womens'Health Initiative (WHI), and a breast cancer scan at the University of Cambridge (UK). We propose to expand the BPC3 to serve as a test set for SNPs identified in the scans other than the CGEMS scan, and to examine gene-environment interactions in the SNPs identified in CGEMS and other studies. We also propose to take advantage of the size of the BPC3 to conduct genome-wide association studies of Estrogen Receptor negative (ER-) breast cancer, and Aggressive Prostate Cancer. There is evidence that ER- breast cancer has a different etiology than ER+ breast cancer, and similarly, the genetic risk factors for Aggressive Prostate Cancer may be different than those for non-Aggressive disease. Single studies do not have power to address these important subtypes. We will replicate findings for Aggressive Prostate Cancer in additional cases from the BPC3, and for ER- breast cancer replicate in 2500 cases from the Breast Cancer Association Consortium (BCAC). The alliance of the BPC3 with the BCAC will facilitate communications and pooled analyses between the two largest sets of studies examining inherited susceptibility to breast cancer.
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