title: 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.
authors.affiliation: Dipartimento di Biologia, University of Pisa, Via Derna, 1, 56126 Pisa, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Landi
authors.forename: Federica
authors.initials: F
authors.lastname: Gemignani
authors.forename: Alessio
authors.initials: A
authors.lastname: Naccarati
authors.forename: Barbara
authors.initials: B
authors.lastname: Pardini
authors.forename: Pavel
authors.initials: P
authors.lastname: Vodicka
authors.forename: Ludmila
authors.initials: L
authors.lastname: Vodickova
authors.forename: Jan
authors.initials: J
authors.lastname: Novotny
authors.forename: Asta
authors.initials: A
authors.lastname: Försti
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.forename: Federico
authors.initials: F
authors.lastname: Canzian
authors.forename: Stefano
authors.initials: S
authors.lastname: Landi
mesh_terms: D000368:Aged; D001483:Base Sequence; D001665:Binding Sites; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D017931:DNA Primers; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D017931:DNA Primers; D035683:MicroRNAs