A functional polymorphism in the miR-146a gene and age of familial breast/ovarian cancer diagnosis

AG to C polymorphism (rs2910164) is located within the sequence of miR-146a precursor, which leads to a change from a G: U pair to a C: U mismatch in its stem region. The predicted miR-146a target genes include BRCA1 and BRCA2, which are key breast and ovarian cancer genes. To examine whether rs2910164 plays any role in breast and/or ovarian cancer, we studied associations between this polymorphism and age of diagnosis in 42 patients with familial breast cancer and 82 patients with familial ovarian cancer. Breast cancer patients who had at least one miR-146a variant allele were diagnosed at an earlier age than with no variant alleles (median age 45 versus 56, P = 0.029) and ovarian cancer patients who had at least one miR-146a variant allele were diagnosed younger than women without any variant allele (median age 45 versus 50, P = 0.014). In further functional analysis, we found that the variant allele displayed increased production of mature miR-146a from the precursor microRNA compared with the common allele. Consistent with the target prediction, in a target in vitro assay, we observed that miR-146a could bind to the 3' untranslated regions (UTRs) of BRCA1 and BRCA2 messenger RNAs (mRNAs) and potentially modulate their mRNA expression. Intriguingly, the binding capacity between the 3' UTR of BRCA1 and miR-146a was statistically significantly stronger in variant C allele than those in common G allele (P = 0.046). Taken together, our data suggest that breast/ovarian cancer patients with variant C allele miR-146a may have high levels of mature miR-146 and that these variants predispose them to an earlier age of onset of familial breast and ovarian cancers.