Polymorphisms within micro-RNA-binding sites and risk of sporadic colorectal cancer

Abstract

Recent evidence indicate that small non-coding RNA molecules, called micro-RNAs (miRNAs), can bind to the 3' untranslated regions (UTRs) of messenger RNAs 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 deregulation 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' UTRs of 104 genes candidate for colorectal cancer (CRC) and we identified putative miRNA-binding sites by specialized algorithms (PicTar, DianaMicroT, miRBase, miRanda, TargetScan and microInspector). Fifty-seven single-nucleotide polymorphisms (SNPs) were identified in miRNA-binding sites. 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 eight common polymorphisms that 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 [odds ratio (OR) = 2.74; 95% confidence interval (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). These results are the first reporting positive association between miRNA-binding SNPs sequences and cancer risk.

A genetic variant in the pre-miR-27a oncogene is associated with a reduced familial breast cancer risk

“…Differential miR-NA expression could be caused by sequence variations, such as mutations and SNPs. So far, SNPs in the miRNA target sites have been widely studied [27][28][29], but the association between SNPs in miRNAs and familial breast cancer risk remains still largely unknown.…”

“…Although the single nucleotide polymorphisms (SNPs) in miRNAs target sites have been studied [27][28][29], the effects of SNPs in miRNAs remain largely unknown. It motivated us to explore polymorphisms in the breast cancer-related miRNA genes and investigate their associations with familial breast cancer risk.…”

MicroRNAs in Colorectal Cancer: Translation of Molecular Biology into Clinical Application

“…Regarding CRC, out of eight candidates predicted by computer simulation, the two genes for CD86, a costimulatory ligand on lymphocytes, and for the insulin receptor carry an SNP that are significantly associated with the risk of sporadic CRC (odds ratios 2.74 and 1.94, respectively) [46]. However, the biological relevance of these SNPs has not yet been confirmed by functional in vitro studies.…”

The impact of microRNAs and alternative splicing in pharmacogenomics

“…Polymorphisms in miRNA target sites of protein-coding genes that are associated to cancer, [58][59][60] hypertension, 61 asthma, 62 cardiovascular disease 63 and polymorphisms in microRNAs that are associated with schizophrenia 40 were also described.…”