Abstract
Genetic variations in 3′ untranslated regions of target genes may affect microRNA binding, resulting in differential protein expression. microRNAs regulate DNA repair, and single-nucleotide polymorphisms in miRNA binding sites (miRSNPs) may account for interindividual differences in the DNA repair capacity. Our hypothesis is that miRSNPs in relevant DNA repair genes may ultimately affect cancer susceptibility and impact prognosis.In the present study, we analysed the association of polymorphisms in predicted microRNA target sites of double-strand breaks (DSBs) repair genes with colorectal cancer (CRC) risk and clinical outcome. Twenty-one miRSNPs in non-homologous end-joining and homologous recombination pathways were assessed in 1111 cases and 1469 controls. The variant CC genotype of rs2155209 in MRE11A was strongly associated with decreased cancer risk when compared with the other genotypes (OR 0.54, 95% CI 0.38–0.76, p = 0.0004). A reduced expression of the reporter gene was observed for the C allele of this polymorphism by in vitro assay, suggesting a more efficient interaction with potentially binding miRNAs. In colon cancer patients, the rs2155209 CC genotype was associated with shorter survival while the TT genotype of RAD52 rs11226 with longer survival when both compared with their respective more frequent genotypes (HR 1.63, 95% CI 1.06-2.51, p = 0.03 HR 0.60, 95% CI 0.41–0.89, p = 0.01, respectively).miRSNPs in DSB repair genes involved in the maintenance of genomic stability may have a role on CRC susceptibility and clinical outcome.
Highlights
Colorectal cancer (CRC) is among the most frequent malignancies worldwide and is the third highest cause of cancer mortality among men and women [1]
Since the majority of the SNPs are not represented in the Caucasian population, only six polymorphisms in four genes (XRCC4, XRCC5, LIG4, and NHEJ1) passing the selection criteria were included in the study
The strongest association with CRC susceptibility was observed for rs2155209 in MRE11A, a gene involved in homologous recombination (HRe)
Summary
Colorectal cancer (CRC) is among the most frequent malignancies worldwide and is the third highest cause of cancer mortality among men and women [1]. Though CRC detected at an early stage can be successfully removed, cancers undetected until an advanced stage with metastases remain incurable [2]. The growing incidence of CRC (2001– 2011 growth index 6.0%) was accompanied by a relatively low rate of early detection of the disease [3]. The molecular etiology of CRC has been explored extensively, revealing that this cancer develops from an accumulation of genomic mutations. Accumulating cellular DNA damage, if not correctly repaired, can lead to genomic instability, apoptosis or senescence and may predispose the organism to various disorders including cancers. There is a large body of evidence on the associations between DNA repair and the risk of cancer, including CRC [5]
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