Polymorphic micro-RNA targets and risk of colorectal cancer

Recent evidence indicate that small non-coding RNA molecules, called micro-RNAs (miRNA), can bind to the 3’UTRs of mRNAs and interfere with their translation, thereby regulating cell growth, differentiation, apoptosis, and tumorigenesis. Genetic polymorphisms can reside on miRNA binding sites. Thus, it is conceivable that the miRNA regulation may be affected by polymorphisms on the 3’ UTRs. Since gene de-regulation is one of the key mechanisms by which cells can progress to cancer, we hypothesize that common polymorphisms within miRNA target binding sites could play a role in the individual risk of cancer. In the present study, we selected the 3’UTR regions of 129 genes candidate for colorectal cancer (CRC) and we identified putative miRNA binding sites by specialized algorithms (PicTar, DianaMicroT, miRBase, miRanda, TargetScan, and microInspector). We evaluated the SNPs for their ability to affect the binding of the miRNA with its target, by assessing the variation of Gibbs free energy between the two alleles of each SNP. We found 15 common polymorphisms. We added to this list 8 SNPs in miRNA sequences. All the polymorphisms were further investigated by a case-control association studies. The study was carried out on a series of cases and controls from Czech Republic, a population with the highest worldwide incidence of CRC. We found statistically significant associations between risk of CRC and variant alleles of CD86 (OR=2.74 95%CI=1.24-6.04, for the variant homozygotes) and INSR genes (OR=1.94; 95%CI=1.03-3.66, for the variant homozygotes). Then, these two polymorphisms were genotyped in three different populations: Spanish, Italian, and German.The statistical analyses for all the samples (Czech, Spanish, Italian, and German) confirmed the assciation between risk of CRC and the polymorphisms in CD86 and INSR. These results are the first reporting positive association between miRNA-binding SNPs sequences and cancer risk.