We propose to continue follow-up and activities of the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). The BPC3 includes the American Cancer Society Cancer Prevention Study-II (CPS-II), the Alpha-Tocopherol, Beta-Carotene Study (ATBC), the European Prospective Investigation of Cancer (EPIC), the Health Professionals Follow-up Study (HPFS), the Multiethnic Cohort (MEC), the Nurses' Health Studies I and II (NHS and NHSII), the Physician's Health Study (PHS), the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), and the Women's Health Study (WHS). This international consortium has been established over the last 4 years, and is nearing completion of the assessment of the initial 51 candidate genes in the steroid hormone metabolism and IGF pathways with risk of breast and prostate cancer, as well as single nucleotide polymorphisms (SNPs) in 22 additional genes in these and other important pathways. In the first phase of the ongoing study, resequencing and genotyping data on these candidates were obtained, and tag-SNPs selected in these genes; these data are available to the research community on a public website. Genotyping of these SNPs in over 7,000 cases of breast cancer has been completed or is nearing completion. We have established a database at a breast cancer data coordinating center. With the accrual of additional cases by mid-2007, we expect that this database can be expanded to 14,000 cases of breast cancer. Starting in 2005, the NCI Cancer - Genetic Markers of Susceptibility (CGEMS) project has been conducting genome-wide association studies (GWAS) for breast cancer in the NHS, with replication for SNPs highly ranked in the scan in the other studies of the BPC3. Other GWAS are ongoing, including a breast cancer scan using pooled DNAs in the Women's Health Initiative (WHI) and a breast cancer scan at the University of Cambridge (UK). Infrastructure is now needed to rapidly verify findings in large independent data sets, to determine the role of genetic determinants in important clinical sub-types, and to identify gene-environment interactions. We propose to expand the BPC3 to serve as a rapid verification 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 as being associated with breast cancer. With the completion of GWAS for breast cancer, there are important remaining questions that the BPC3 is uniquely positioned to answer. Estrogen receptor negative (ER-) breast cancers have specific epidemiologic characteristics and greater lethality, but the current generation of scans is underpowered to discover gene variants associated with these tumors. No single study is likely to have enough cases of this cancer subtype to perform a GWAS -- by pooling cases across the BPC3 studies we can achieve adequate power to discover genetic variation that gives rise to ER- breast cancer. HYPOTHESES: 1. The inherited germline predictors of clinically important cancer subtypes, such as ER- breast cancer, are different than for breast cancer overall. 2. SNPs identified as being robustly associated with total breast cancer, or its subtypes, have different effects within strata of defined environmental and lifestyle risk factors for breast cancer. SPECIFIC AIMS: To examine the above hypotheses we propose to: 1. Continue and expand our collaborative database to include over 14,000 cases of breast cancer with matched controls. 2. Genotype the existing and additional cases and controls added to the database for SNPs identified through the CGEMS and other genome-wide association studies as being likely to be causally associated with these cancers. 3. Assess whether the effects of the SNPs identified as likely to be causal vary according to established environmental and lifestyle risk factors. 4. Conduct a GWAS of ER- breast cancer in 1300 White cases and controls contributed by the NHS, CPS-II, WHS, EPIC, PLCO, and MEC studies. We will confirm highly associated SNPs in 2500 ER- cases and controls in the Breast Cancer Association Consortium (BCAC). 5. Assess the generalizability of these findings in non-White women from the MEC and, to the extent available, the other cohorts.

Christine Berg (NCI, DCP)
Stephen Chanock (NCI, DCEG)
Robert Hoover (NCI, DCEG)
Study center PI (TBD)
Meredith Yeager (NCI, CGF)
Regina Ziegler (NCI, DCEG)