The Carolina Breast Cancer Study (CBCS) is a comprehensive, interdisciplinary investigation into the causes of breast cancer in African American and white women. A major focus of the CBCS is to understand genetic susceptibility. Our goal is to conduct the first comprehensive, population-based study of genetic risk factors for in situ and invasive breast cancer in African American and white women. Our recent results have shown that germline mutations in BRCA genes are rare in breast cancer patients. Common inherited polymorphisms in metabolism genes play a role in a much larger number of cases. To date, we have investigated hormone metabolism, carcinogen metabolism, and cell cycle control. We propose here to expand our study of genetic susceptibility to include DNA repair genes, and potential interactions between these genes and exposure to environmental factors. Our preliminary data indicates that polymorphisms in the base excision repair gene, XRCC1, and the double-strand break repair gene, XRCC3, are susceptibility genes for breast cancer. During Phase 1 of the CBCS (1993-1996), 861 cases of invasive breast cancer and 790 population controls were enrolled. During Phase 2 (1996-2000), 890 cases of invasive breast cancer, 514 cases of in situ breast cancer, and 1232 controls were enrolled. After enrolling additional controls, the total number of participants is expected to be 2265 cases and 2086 controls. African Americans comprise 44 percent of invasive cases and 21 percent of in situ cases. Controls are frequency matched to cases based upon age and race. CBCS participants complete in-depth interviews covering known and potential risk factors for breast cancer. Blood samples are collected for extraction of lymphocyte DNA. DNA samples and exposure histories are available from 2147 cases and 2021 controls. The current proposal provides for statistical and laboratory analyses using previously collected DNA samples and exposure information from the CBCS.
The Specific Aims are to conduct high throughput genotyping for single nucleotide polymorphisms in genes involved in the principal DNA repair Pathways: Base excision repair (XRCC], APEI, HOGG], Pol Beta); nucleotide excision repair (XPA, XPD, XPF, ERCC1); double strand break repair (XRCC3, XRCC4); nonhomologous end joining (DNA PK, DNA ligase/); direct repair (MGMT, AGT). Main effects for each genetic locus will be estimated, as well as the combined effects of multiple genes (gene-gene interaction) and the joint effects of genetic and environmental factors (gene-environment interaction). The study will provide important information regarding genetic susceptibility to breast cancer in African American and white women, and help to clarify the role of ionizing radiation, smoking and other environmental exposures in the etiology of breast cancer. In addition, we propose to extend our data collection and obtain updated treatment and outcome information on breast cancer cases. This information will allow us to evaluate novel hypotheses related to the role of DNA repair in response to adjuvant chemotherapy and radiation treatment, and to generate pilot data for subsequent grant applications.
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