A haplotype-based case-control study of BRCA1 and sporadic breast cancer risk

Rare, highly penetrant germ line mutations in BRCA1 strongly predispose women to a familial form of breast and ovarian cancer. Whether common variants (either coding or noncoding) at this locus contribute to the more common form of the disease is not yet known. We tested common variation across the BRCA1 locus in African American, Native Hawaiian, Japanese, Latino, and White women in the Multiethnic Cohort Study. Specifically, 28 single nucleotide polymorphisms (SNPs) spanning the BRCA1 gene were used to define patterns of common variation in these populations. The majority of SNPs were in strong linkage disequilibrium with one another, indicating that our survey captured most of the common inherited variation across this gene. Nine tagging SNPs, including five missense SNPs, were selected to predict the common BRCA1 variants and haplotypes among the non-African American groups (five additional SNPs were required for African Americans) and genotyped in a breast cancer case-control study nested in the Multiethnic Cohort Study (cases, n = 1,715; controls, n = 2,502). We found no evidence for significant associations between common variation in BRCA1 and risk of breast cancer. Given the large size of our study population and detailed analysis of the locus, this result indicates either that common variants in BRCA1 do not substantially influence sporadic breast cancer risk, or that unmeasured heterogeneity in the breast cancer phenotype or unmeasured interactions with genetic or environmental exposures obscure our ability to detect any influence that may be present.