title: Variations in mismatch repair genes and colorectal cancer risk and clinical outcome.
abstract: DNA mismatch repair (MMR) deficiency is one of the best understood forms of genetic instability in colorectal cancer (CRC). CRC is routinely cured by 5-fluorouracil (5-FU)-based chemotherapy, with a prognostic effect and resistance to such therapy conferred by MMR status. In this study, we aimed to analyse the effect of genetic variants in classical coding regions or in less-explored predicted microRNA (miRNA)-binding sites in the 3' untranslated region (3'UTR) of MMR genes on the risk of CRC, prognosis and the efficacy of 5-FU therapy. Four single nucleotide polymorphisms (SNPs) in MMR genes were initially tested for susceptibility to CRC in a case-control study (1095 cases and 1469 healthy controls). Subsequently, the same SNPs were analysed for their role in survival on a subset of patients with complete follow-up. Two SNPs in MLH3 and MSH6 were associated with clinical outcome. Among cases with colon and sigmoideum cancer, carriers of the CC genotype of rs108621 in the 3'UTR of MLH3 showed a significantly increased survival compared to those with the CT + TT genotype (log-rank test, P = 0.05). Moreover, this polymorphism was also associated with an increased risk of relapse or metastasis in patients with heterozygous genotype (log-rank test, P = 0.03). Patients carrying the CC genotype for MSH6 rs1800935 (D180D) and not undergoing 5-FU-based chemotherapy showed a decreased number of recurrences (log-rank test, P = 0.03). No association with CRC risk was observed. We provide the first evidence that variations in potential miRNA target-binding sites in the 3'UTR of MMR genes may contribute to modulate CRC prognosis and predictivity of therapy.
authors.affiliation: Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14200 Prague, Czech Republic, Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Katerinska 32, 12800 Prague, Czech Republic, vpolakova@biomed.cas.cz.
authors.forename: Veronika
authors.initials: V
authors.lastname: Vymetalkova
authors.affiliation: Human Genetics Foundation, Via Nizza 52, 10126 Turin, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pardini
authors.affiliation: Human Genetics Foundation, Via Nizza 52, 10126 Turin, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Rosa
authors.affiliation: Human Genetics Foundation, Via Nizza 52, 10126 Turin, Italy, Department of Medical Sciences, University of Turin, Via Verdi 8, 10124 Turin, Italy.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Di Gaetano
authors.affiliation: Department of Oncology, First Faculty of Medicine, Charles University, Katerinska 32, 12800 Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Novotny
authors.affiliation: Department of Surgery, First Faculty of Medicine, Charles University, Katerinska 32, 12800 Prague, Czech Republic and.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Levy
authors.affiliation: Department of Surgery, First Faculty of Medicine, Charles University, Katerinska 32, 12800 Prague, Czech Republic and Thomayer University Hospital, Videnska 800, 14059 Prague, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Buchler
authors.affiliation: Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14200 Prague, Czech Republic, Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Katerinska 32, 12800 Prague, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Slyskova
authors.affiliation: Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14200 Prague, Czech Republic, Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Katerinska 32, 12800 Prague, Czech Republic.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Vodickova
authors.affiliation: Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14200 Prague, Czech Republic, Human Genetics Foundation, Via Nizza 52, 10126 Turin, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Naccarati
authors.affiliation: Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14200 Prague, Czech Republic, Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Katerinska 32, 12800 Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Vodicka
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D045643:DNA Repair Enzymes