Carcinogenesis Advance Access originally published online on January 12, 2008
Carcinogenesis 2008 29(3):579-584; doi:10.1093/carcin/bgm304
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Polymorphisms within micro-RNA-binding sites and risk of sporadic colorectal cancer
1 Dipartimento di Biologia, University of Pisa, Via Derna, 1, 56126 Pisa, Italy
2 Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
3 Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Science of Czech Republic, Videnska 1083, 14220 Prague 4, Czech Republic
4 Centre of Occupational Health, National Institute of Public Health, Srobarova, 100 42 Prague 10, Czech Republic
5 Department of Oncology, First Faculty of Medicine, Charles University, 12000 Prague, Czech Republic
6 Oncology Centre, Hospital 26205 Pribram, Pribram, Czech Republic
7 Center for Family and Community Medicine, Karolinska Institute, SE-17177 Huddinge, Sweden
* To whom correspondence should be addressed. Tel: +39 050 2211505; Fax: +39 0502211527;Email: slandi{at}biologia.unipi.it
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.
Abbreviations: CRC, colorectal cancer; CI, confidence interval; mRNA, messenger RNA; miRNA, micro-RNA; MAF, minor allele frequency; nt, nucleotide; OR, odds ratio; SNP, single-nucleotide polymorphism; UTR, untranslated region
Received October 24, 2007; revised December 6, 2007; accepted December 22, 2007.
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