Polymorphisms in miRNA-binding sites of nucleotide excision repair genes and colorectal cancer risk

Abstract

Reduced DNA repair capacity and DNA damage accumulation may lead to cancer development. Regulation of and coordination between genes involved in DNA repair pathways is fundamental for maintaining genome stability, and post-transcriptional gene regulation by microRNAs (miRNAs) may therefore be of particular relevance. In this context, the presence of single nucleotide polymorphisms (SNPs) within the 3'untranslated regions of target DNA repair genes could alter the binding with specific miRNAs, modulating gene expression and ultimately affecting cancer susceptibility. In this study, we investigated the role of genetic variations in miRNA-binding sites of nucleotide excision repair (NER) genes in association with colorectal cancer (CRC) risk. From 28 NER genes, we screened among SNPs residing in their 3'untranslated regions and simultaneously located in miRNA-binding sites, with an in silico approach. Through the calculation of different binding free energy according to both alleles of identified SNPs, and with global binding free energies median providing a threshold, we selected nine NER gene variants. We tested those SNPs in 1098 colorectal cancer cases and 1469 healthy controls from the Czech Republic. Rs7356 in RPA2 and rs4596 in GTF2H1 were associated with colorectal cancer risk. After stratification for tumor location, the association of both SNPs was significant only for rectal cancer (rs7356: OR 1.52, 95% CI 1.02-2.26, P = 0.04 and rs4596: OR 0.69, 95% CI 0.50-0.94, P = 0.02; results not adjusted for multiple testing). Variation in miRNA target binding sites in the 3'untranslated region of NER genes may be important for modulating colorectal cancer risk, with a different relevance according to tumor location.

Variation within 3′-UTRs of Base Excision Repair Genes and Response to Therapy in Colorectal Cancer Patients: A Potential Modulation of microRNAs Binding

“…Unlike our previous studies (18,19,35), we did not observe any association of these 3 0 -UTR-localized SNPs with risk of colorectal cancer. With a study group of 1,095 cases and 1,469 controls, we had more than 80% power to detect an association for a recessive/dominant model with OR > 1.30 at a ¼ 0.05 (with MAF ¼ 0.30; power calculation by NAME software).…”

“…An increasing body of evidence has indicated miRNAs as cancer diagnostic, prognostic, and predictive clinical biomarkers (26,27). The presence of SNPs within the 3 0 -UTRs of target DNA repair genes that alter the binding with specific miRNAs and modulate gene expression, may ultimately affect cancer susceptibility (18). Less is known about the effect of variations in such genes on patient survival and on the effect of therapy via miRNA modulation (28).…”

“…We did not rank and test SNPs according to allele-specific Gibbs-free binding energy, as did previous studies (18,20), but we have analyzed systematically all polymorphisms retrieved in the 3 0 -UTR of BER genes with an adequate MAF in the population. An additional software available online (Mirnsnpscore; http://www.bigr .medisin.ntnu.no/mirsnpscore/), based on in silico predictions of SNP effects on miRNA-based gene regulation, was also queried to verify the regulatory effect of the selected SNPs.…”

“…When SNPs occur in 3 0 -UTRs, they may interfere with mRNA stability and translation by altering polyadenylation, protein::mRNA and miRNA::mRNA regulatory interactions, which may lead to altered cancer susceptibility (15)(16)(17). Polymorphic target sites for miRNAs may play a role in modulating important pathways such as DNA repair (18), thereby potentially affecting the individual risk of colorectal cancer (19,20). The aim of the present study was to investigate the role of polymorphisms in potential miRNA-binding sites within the 3 0 -UTRs of BER genes in modulating the risk of colorectal cancer, its progression, and prognosis.…”

SNP at miR-483-5p-binding site in the 3'-untranslated region of the BSG gene is associated with susceptibility to esophageal cancer in a Chinese population

“…Some of these SNPs have been confirmed to alter the expression of target genes by modulating the binding ability, and display a significant association with susceptibility to malignancy (Brendle et al, 2008;Naccarati et al, 2012). Ye et al (2014) reported that SNPs in the microRNA-binding sites in the ITGB1 and ITGB3 3'-UTR were associated with an increased risk of colorectal cancer.…”