PI: Kathi Malone PhD
While disease-associated mutations that result in protein truncation are easy to recognize, variants affecting single bases, often causing missense changes or single amino loss, are largely of unknown clinical significance. The problem is particularly significant for African-American women, as few studies have addressed the role of BRCA1/BRCA2 susceptibility in this underserved minority and common polymorphisms have yet to be established. Indeed, studies of BRCA1/BRCA2 frequency and distribution in African-American women involve only a small number of highly selected women.
The aims of this project are to conduct a series of statistical and laboratory analyses, using data and samples from a recently completed population-based study of breast cancer, to investigate the clinical significance of missense changes in BRCA1 and BRCA2 in African-American women. We will analyze all missense changes observed in all 696 African-American women in the CARE study who are already tested for BRCA1 and BRCA2 mutations using a series of newly available computational tools to predict which variants are most likely to be disease-associated. We will test DNA samples from the remaining African-American control women from the CARE study who gave blood but have not yet been genotyped (n = 238 women) for the presence or absence of “candidate” missense changes. We will examine results from the expanded case-control study of 484 African-American cases and 451 controls, combined with predictive measures, to establish a rank order of “candidates” most likely to be disease-associated in African-American women. Examination of the candidates using laboratory-based functional assays will assist in determining if a given variant affects protein activity, secondary structure or co-factor binding, message stability or production.
Given the increasing number of U.S. women receiving clinical testing for these genes, this project’s ultimate contribution would provide clarification regarding the likely disease-related significance of a subset of missense variants. These data will be used to prioritize variants for functional assay testing, which in turn will provide data for genetic counselors and clinicians seeking to determine an individual patient’s BRCA1/BRCA2 risk profile.