MiRNA disrupting variants and breast cancer risk

Genetic markers identifying women at increased risk of developing breast cancer exist, yet the majority of genetic risk remains elusive. While numerous BRCA1 coding sequence mutations are associated with breast cancer risk, mutations in BRCA1 account for < 5% of all breast cancer risk. Since 3' untranslated region (3'UTR) polymorphisms disrupting microRNA (miRNA) binding sites can be functional and can act as genetic markers of cancer risk, we tested the hypothesis that such polymorphisms in the 3'UTR of BRCA1 and haplotypes containing these functional 3'UTR variants may be associated with breast cancer risk.;We identified three 3'UTR BRCA1 variants that are polymorphic in breast cancer populations. One, rs8176318-A/A, shows significant cancer association for African Americans and specifically predicts for the risk of developing triple negative breast cancer for African Americans (p =0.03, p=0.02, respectively). Haplotype analysis revealed breast cancer patients (n=221) harbor five rare haplotypes including these 3'UTR·variants not generally found among controls (9.50% for all breast cancer chromosomes, 0.11% for control chromosomes, p<0.0001). Furthermore, these rare haplotypes are not biomarkers for BRCA1 coding region mutations, as they are found rarely in BRCA1 mutant breast cancer patients (1/129 patients= 0.78%; or 1/258 chromosomes).;Because a derived allele at rs1060915 is a component of all identified five rare BRCA1 haplotypes and significantly associates with cancer when in homozygosity for African Americans and for TN breast cancer among African Americans (p=0.01, p=0.005, respectively), we assessed the affects of rs1060915 on gene regulation in vitro. In addition coding sequence SNPs, like rs1060915, can be located in miRNA binding sites and influence tumor susceptibility. Functional analysis showed the derived allele specifically alters miR-7 binding, a miRNA controlled by BRCA1 expression.;We identified rare BRCA1 haplotypes, including 3'UTR and coding sequence SNPs that associate with breast cancer risk, are infrequently found in the general population and significantly enriched for in breast cancer patients, especially TN and ER/PR+ breast cancer patients. The rare haplotypes include a breast cancer associated coding sequence SNP that alters binding of miR-7 and affects BRCA1 expression. These rare BRCA1 haplotypes may represent new genetic markers of increased breast cancer risk.