Carcinogenesis Advance Access first published online on July 27, 2008
This version published online on August 11, 2008
Carcinogenesis, doi:10.1093/carcin/bgn172
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A Functional Polymorphism in the miR-146a Gene and Age of Familial Breast/Ovarian Cancer Diagnosis
1 Department of Cancer Prevention and Control
2 Department of Cancer Genetics
3 Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263
Request for reprints: Hua Zhao, Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Elm and Carlton Streets, Basic Science 704, Buffalo, NY 14263. Phone: 716-845-3103; Fax: 716-845-1356; E-mail: hua.zhao{at}roswellpark.org.
A G 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 exam 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 vs 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 vs 50, p = 0.014). In further functional analysis, we found that the variant allele displayed increased production of mature miR-146a from the precursor miRNA compared to the common allele. Consistent with the target prediction, in a target in vitro assay we observed that miR-146a could bind to the 3’UTRs of BRCA1 and BRCA2 mRNAs and potentially modulate their mRNA expression. Intriguingly, the binding capacity between the 3’UTR of BRCA1 and miR-146a were 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 cancer.
Key Words: miR-146a • polymorphism • breast cancer • ovarian cancer • age of diagnosis
Grant support: The work was supported by two awards from the Roswell Park Alliance Foundation
Received May 1, 2008; revised June 25, 2008; accepted July 15, 2008.
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