title: Double-strand break repair and colorectal cancer: gene variants within 3' UTRs and microRNAs binding as modulators of cancer risk and clinical outcome.
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.
authors.affiliation: Molecular and Genetic Epidemiology Research Unit, Human Genetics Foundation, Turin, Italy.|Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Prague, Czech Republic.
authors.forename: Alessio
authors.initials: A
authors.lastname: Naccarati
authors.affiliation: Genomic Variation in Human Populations and Complex Diseases Research Unit, Human Genetics Foundation, Turin, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Rosa
authors.affiliation: Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Prague, Czech Republic.|Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Veronika
authors.initials: V
authors.lastname: Vymetalkova
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Barone
authors.affiliation: Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Prague, Czech Republic.|Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Katerina
authors.initials: K
authors.lastname: Jiraskova
authors.affiliation: Genomic Variation in Human Populations and Complex Diseases Research Unit, Human Genetics Foundation, Turin, Italy.|Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Di Gaetano
authors.affiliation: Department of Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Novotny
authors.affiliation: Department of Surgery, First Faculty of Medicine, Charles University and Thomayer University Hospital, Prague, Czech Republic.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Levy
authors.affiliation: Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Prague, Czech Republic.|Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Vodickova
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Gemignani
authors.affiliation: Department of Oncology, Thomayer Hospital and First Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Buchler
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Landi
authors.affiliation: Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Prague, Czech Republic.|Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Vodicka
authors.affiliation: Genomic Variation in Human Populations and Complex Diseases Research Unit, Human Genetics Foundation, Turin, Italy.|Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pardini
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D000076228:MRE11 Homologue Protein / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D051721:Rad52 DNA Repair and Recombination Protein / Q000235:genetics*; D015996:Survival Rate; D055815:Young Adult
chemical_list: D020413:3' Untranslated Regions; D014408:Biomarkers, Tumor; C121766:MRE11 protein, human; D035683:MicroRNAs; C497194:RAD52 protein, human; D051721:Rad52 DNA Repair and Recombination Protein; D000076228:MRE11 Homologue Protein
keywords: 3′UTR polymorphisms; MRE11A; colorectal cancer risk and clinical outcomes; double-strand break repair (DSBR) genes; miRNA binding sites