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. 2016 Apr 26;7(17):23156-69.
doi: 10.18632/oncotarget.6804.

Double-strand break repair and colorectal cancer: gene variants within 3' UTRs and microRNAs binding as modulators of cancer risk and clinical outcome

Alessio Naccarati  1   2 , Fabio Rosa  3 , Veronika Vymetalkova  2   4 , Elisa Barone  5 , Katerina Jiraskova  2   4 , Cornelia Di Gaetano  3   6 , Jan Novotny  7 , Miroslav Levy  8 , Ludmila Vodickova  2   4 , Federica Gemignani  5 , Tomas Buchler  9 , Stefano Landi  5 , Pavel Vodicka  2   4 , Barbara Pardini  3   6
Affiliations

Double-strand break repair and colorectal cancer: gene variants within 3' UTRs and microRNAs binding as modulators of cancer risk and clinical outcome

Alessio Naccarati et al. Oncotarget. .

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.

Keywords: 3′UTR polymorphisms; MRE11A; colorectal cancer risk and clinical outcomes; double-strand break repair (DSBR) genes; miRNA binding sites.

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Conflict of interest statement

The authors declare that there are no conflicts of interest.

Figures

Figure 1
Figure 1. Kaplan-Meier OS curves for RAD52 rs11226 in all CRC patients
MST = median survival time.
Figure 2
Figure 2. Kaplan-Meier OS curves for MRE11A rs2155209 in colon cancer patients
MST = median survival time.
Figure 3
Figure 3. Data show mean values of luminescence activity, normalized to Renilla luciferase levels, (FLUC/RLUC) from four independent experiments
MRE11A expression show a statistical significant (p = 0.007) decrease of about 14% in presence of the rs2155209 C-variant, compared to the expression obtained with the T-variant.
See this image and copyright information in PMC

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