Investigation of a novel +ACA BRCA1 promoter polymorphism and its impact on the breast cancer susceptibility phenotype

We identified a +ACA BRCA1 promoter polymorphism located -600bp from the BRCA1 exon1a transcriptional start site. The +ACA insertion creates a consensus FAC1 transcriptional repressor binding site (AACAACAC). We determined the frequency of the +ACA allele in 1760 DNA samples from the general population and breast disease patients. We observed a significantly higher allelic frequency of the +ACA BRCA1 promoter in African-American cases (27%) compared to African-American controls (17%, P=0.0005), while no significant difference among Caucasian cases and controls were observed (34% versus 37%, P=0.50). Furthermore, we observed statistically significant reduction in functional activity in the +ACA polymorphic promoter in both the absence and presence of exogeneous FAC1 compared to the wild-type BRCA1 promoter. The results of the study enabled expansion of the two-hit model of breast cancer susceptibility to include a FAC1-mediated BRCA1 silencing in patients that carry the BRCA1 promoter polymorphism.