Association between genetic polymorphisms in DNA mismatch repair‐related genes with risk and prognosis of head and neck squamous cell carcinoma

• Published in: International journal of cancer 2015-08, Vol.137 (4), p.810-818
• Main Authors: Nogueira, Guilherme Augusto Silva, Lourenço, Gustavo Jacob, Oliveira, Camila Borges Martins, Marson, Fernando Augusto Lima, Lopes‐Aguiar, Leisa, Costa, Ericka Francislaine Dias, Lima, Tathiane Regine Penna, Liutti, Vitor Teixeira, Leal, Frederico, Santos, Vivian Castro Antunes, Rinck‐Junior, José Augusto, Lima, Carmen Silvia Passos
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adolescent; Adult; Aged; Aged, 80 and over; Cancer; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Clinical outcomes; Disease-Free Survival; DNA mismatch repair; DNA repair; DNA Repair Enzymes - genetics; DNA-Binding Proteins - genetics; EXO1; Exodeoxyribonucleases - genetics; Female; Genetic Association Studies; Genotype; Genotype & phenotype; Head & neck cancer; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - pathology; head and neck squamous cell carcinoma; Humans; laryngeal squamous cell carcinoma; Male; Medical prognosis; Medical research; Middle Aged; MLH1; MSH2; MSH3; MutL Protein Homolog 1; MutS Homolog 2 Protein - genetics; MutS Homolog 3 Protein; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - pathology; Nuclear Proteins - genetics; Patients; Polymorphism; Polymorphism, Single Nucleotide; Prognosis; risk; SNP; Squamous Cell Carcinoma of Head and Neck
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.29435

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. What is new? Not all smokers get cancer: the disease results from a combination of environmental and genetic factors. Mutations that hamper DNA repair could contribute, and in this paper the authors investigated four such variants. These polymorphisms, they found, could triple the risk of head and neck cancer. Among smokers, the effect was even more pronounced. Thus, these DNA mismatch repair alleles could be useful for predicting patient outcomes.