Double-strand break repair and colorectal cancer: gene variants within 3′ UTRs and microRNAs binding as modulators of cancer risk and clinical outcome
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Alessio Naccarati1,2, Fabio Rosa3, Veronika Vymetalkova2,4, Elisa Barone5, Katerina Jiraskova2,4, Cornelia Di Gaetano3,6, Jan Novotny7, Miroslav Levy8, Ludmila Vodickova2,4, Federica Gemignani5, Tomas Buchler9, Stefano Landi5, Pavel Vodicka2,4,*, Barbara Pardini3,6,*
1Molecular and Genetic Epidemiology Research Unit, Human Genetics Foundation, Turin, Italy
2Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Prague, Czech Republic
3Genomic Variation in Human Populations and Complex Diseases Research Unit, Human Genetics Foundation, Turin, Italy
4Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
5Department of Biology, University of Pisa, Pisa, Italy
6Department of Medical Sciences, University of Turin, Turin, Italy
7Department of Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic
8Department of Surgery, First Faculty of Medicine, Charles University and Thomayer University Hospital, Prague, Czech Republic
9Department of Oncology, Thomayer Hospital and First Faculty of Medicine, Charles University, Prague, Czech Republic
*These authors contributed equally to this work
Alessio Naccarati, e-mail: firstname.lastname@example.org
Keywords: double-strand break repair (DSBR) genes, colorectal cancer risk and clinical outcomes, miRNA binding sites, 3′UTR polymorphisms, MRE11A
Received: July 07, 2015 Accepted: December 09, 2015 Published: December 31, 2015
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.
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