Carcinogenesis Advance Access published online on January 12, 2008
Carcinogenesis, 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 S. Giuseppe 22, 56126 Pisa
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, Prague, Czech Republic
6 Oncology Centre, Hospital Pribram, Pribram, Czech Republic
7 Center for Family and Community Medicine, Karolinska Institute, Huddinge, Sweden
Corresponding author:Stefano Landi, Department of Biology, University of Pisa. Via Derna, 1. 56126 Pisa. e-mail: slandi{at}biologia.unipi.it. Tel.: +39 050 2211505
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 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 8 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 (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). These results are the first reporting positive association between miRNA-binding SNPs sequences and cancer risk.
Key Words: colorectal cancer • single nucleotide polymorphisms • micro-RNA • association study • CD86 • insulin receptor
Received October 24, 2007; revised December 6, 2007; accepted December 22, 2007.
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