Abstract 1170: MicroRNA gene polymorphisms in cancer susceptibility loci 5p12, 8q24 and 11q13

Abstract

Abstract Using Genome Wide Association Studies (GWAS), we and others have previously identified and replicated genetic variations in chromosome 5p12, 8q24 and 11q13. Interestingly, the majority of risk-associated variations map to non-coding regions of the genome and thus, the molecular mechanism of single nucleotide polymorphisms (SNPs) underlying increased cancer risk remains unknown. To assess whether these SNPs could affect the biogenesis and function of non-coding RNA species, such as microRNAs (miRNA), here we assessed miRNA gene polymorphisms in these cancer susceptibility loci. We catalogued two miRNA genes in 5p12, sixteen miRNA genes in 8q24, and seven miRNA genes in 11q13. We re-sequenced the pri- and pre-miRNA genomic sequences in these loci using HapMap DNA samples. As a result, in 8q24 miRNA genes, we identified three new SNPs and confirmed two previously reported SNPs. In 11q13, we identified four genetic variations within different miRNA genes. However, linkage disequilibrium plot analysis of both loci didn't show any statistically significant association of any of these SNPs with their corresponding GWAS signals. Thus, we consider it unlikely that miRNA in these regions are direct downstream effectors of cancer-associated genetic variations. Nevertheless, because these risk loci are prone to genomic instability, we assessed whether the SNPs could affect miRNA gene expression since indirect associations with increased cancer susceptibility can't be excluded. To address this question, we cloned pre-miRNA genes from these loci, with or without genetic variations, into miRNA expression vectors and determined their relative expression in transfected 293T cells. We tested for an 8q24-encoded miRNA (miR-1206) or an 11q13 encoded-miRNA (miR-612) expression using miRNA TaqMan assays, and we found that the G allele polymorphism (rs2114358) in miR-1206 significantly downregulated miRNA expression levels compared to the reference A allele. On the other hand, an rs550894 (C/A) in miR-612 significantly upregulated miRNA expression levels compared to that of the reference C allele. These data indicate that the miRNA SNPs in these loci have indeed functional consequences that lead to dysregulation of miRNA biogenesis. Whether such changes in miRNA expression could also result in increased cancer risk needs to be assessed in future studies by identifying the downstream target genes of these miRNAs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1170. doi:10.1158/1538-7445.AM2011-1170