Evaluation of Genetic Variations in miRNA-Binding Sites of BRCA1 and BRCA2 Genes as Risk Factors for the Development of Early-Onset and/or Familial Breast Cancer

Although genetic markers identifying women at an increased risk of developing breast cancer exist, themajority of inherited risk factors remain elusive. Mutations in the BRCA1/BRCA2 gene confer a substantialincrease in breast cancer risk, yet routine clinical genetic screening is limited to the coding regions and intronexonboundaries, precluding the identification of mutations in noncoding and untranslated regions. Because 3’untranslated region (3’UTR) polymorphisms disrupting microRNA (miRNA) binding can be functional and canact as genetic markers of cancer risk, we aimed to determine genetic variation in the 3’UTR of BRCA1/BRCA2in familial and early-onset breast cancer patients with and without mutations in the coding regions of BRCA1/BRCA2 and to identify specific 3’UTR variants that may be risk factors for cancer development. The 3’UTRs ofthe BRCA1 and BRCA2 genes were screened by heteroduplex analysis and DNA sequencing in 100 patients from46 BRCA1/2 families, 54 non-BRCA1/2 families, and 47 geographically matched controls. Two polymorphismswere identified. SNPs c.*1287C>T (rs12516) (BRCA1) and c.*105A>C (rs15869) (BRCA2) were identified in27% and 24% of patients, respectively. These 2 variants were also identified in controls with no family historyof cancer (23.4% and 23.4%, respectively). In comparison to variations in the 3’UTR region of the BRCA1/2genes and the BRCA1/2 mutational status in patients, there was a statistically significant relationship betweenthe BRCA1 gene polymorphism c.*1287C>T (rs12516) and BRCA1 mutations (p=0.035) by Fisher’s Exact Test.SNP c.*1287C>T (rs12516) of the BRCA1 gene may have potential use as a genetic marker of an increased risk ofdeveloping breast cancer and likely represents a non-coding sequence variation in BRCA1 that impacts BRCA1function and leads to increased early-onset and/or familial breast cancer risk in the Turkish population.