title: Association between genetic polymorphisms in DNA mismatch repair-related genes with risk and prognosis of head and neck squamous cell carcinoma.
abstract: We examined the influence of MLH1 c.-93G>A, MSH2 c.211 + 9C>G, MSH3 c.3133G>A and EXO1 c.1765G>A polymorphisms, involved in DNA mismatch repair (MMR), on head and neck (HN) squamous cell carcinoma (SCC) risk and prognosis. Aiming to identify genotypes, DNA from 450 HNSCC patients and 450 controls was analyzed by PCR-RFLP or real time PCR. MSH2 GG plus MSH3 GG (31.7% vs. 18.7%, p = 0.003) genotypes were higher in laryngeal SCC (LSCC) patients than in controls. Carriers of the respective combined genotype were under a 3.69 (95% CI: 1.54-8.81)-fold increased risk of LSCC. Interactions of tobacco and tobacco plus all the above-mentioned polymorphisms on HNSCC and LSCC risk were also evident in study (p = 0.001). At 60 months of follow-up, relapse-free survival (RFS) was shorter in patients with EXO1 GG genotype (54.8% vs. 61.1%, p = 0.03) and overall survival (OS) was shorter in patients with MSH3 GG genotype (42.8% vs. 52.5%, p = 0.02) compared to those with other genotypes, respectively. After multivariate Cox analysis, patients with EXO1 GG and MSH3 GG genotypes had worst RFS (HR: 1.50, 95% CI: 1.03-2.20, p = 0.03) and OS (HR: 1.59, 95% CI: 1.19-2.13, P = 0.002) than those with the remaining genotypes, respectively. Our data present, for the first time, evidence that inherited MLH1 c.-93G>A, MSH2 c.211 + 9C>G, MSH3 c.3133G>A, and EXO1 c.1765G>A abnormalities of DNA MMR pathway are important determinants of HNSCC, particularly among smokers, and predictors of patient outcomes.
authors.affiliation: Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.
authors.forename: Guilherme Augusto Silva
authors.initials: GA
authors.lastname: Nogueira
authors.affiliation: Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.
authors.forename: Gustavo Jacob
authors.initials: GJ
authors.lastname: Lourenço
authors.affiliation: Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.
authors.forename: Camila Borges Martins
authors.initials: CB
authors.lastname: Oliveira
authors.affiliation: Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.
authors.forename: Fernando Augusto Lima
authors.initials: FA
authors.lastname: Marson
authors.affiliation: Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.
authors.forename: Leisa
authors.initials: L
authors.lastname: Lopes-Aguiar
authors.affiliation: Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.
authors.forename: Ericka Francislaine Dias
authors.initials: EF
authors.lastname: Costa
authors.affiliation: Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.
authors.forename: Tathiane Regine Penna
authors.initials: TR
authors.lastname: Lima
authors.affiliation: Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.
authors.forename: Vitor Teixeira
authors.initials: VT
authors.lastname: Liutti
authors.affiliation: Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.
authors.forename: Frederico
authors.initials: F
authors.lastname: Leal
authors.affiliation: Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.
authors.forename: Vivian Castro Antunes
authors.initials: VC
authors.lastname: Santos
authors.affiliation: Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.
authors.forename: José Augusto
authors.initials: JA
authors.lastname: Rinck-Junior
authors.affiliation: Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.
authors.forename: Carmen Silvia Passos
authors.initials: CS
authors.lastname: Lima
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D018572:Disease-Free Survival; D005090:Exodeoxyribonucleases / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D000074081:MutS Homolog 3 Protein; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; C078444:MSH3 protein, human; D000074081:MutS Homolog 3 Protein; D009687:Nuclear Proteins; C114331:EXO1 protein, human; D005090:Exodeoxyribonucleases; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes
keywords: DNA mismatch repair; EXO1; MLH1; MSH2; MSH3; SNP; head and neck squamous cell carcinoma; laryngeal squamous cell carcinoma; prognosis; risk