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

Int J Cancer. 2015 Aug 15;137(4):810-8. doi: 10.1002/ijc.29435. Epub 2015 Feb 26.

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.

Keywords: DNA mismatch repair; EXO1; MLH1; MSH2; MSH3; SNP; head and neck squamous cell carcinoma; laryngeal squamous cell carcinoma; prognosis; risk.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / pathology
  • DNA Repair Enzymes / genetics*
  • DNA-Binding Proteins / genetics*
  • Disease-Free Survival
  • Exodeoxyribonucleases / genetics*
  • Female
  • Genetic Association Studies
  • Genotype
  • Head and Neck Neoplasms / genetics*
  • Head and Neck Neoplasms / pathology
  • Humans
  • Male
  • Middle Aged
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein / genetics*
  • MutS Homolog 3 Protein
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / pathology
  • Nuclear Proteins / genetics*
  • Polymorphism, Single Nucleotide
  • Prognosis
  • Squamous Cell Carcinoma of Head and Neck

Substances

  • Adaptor Proteins, Signal Transducing
  • DNA-Binding Proteins
  • MLH1 protein, human
  • MSH3 protein, human
  • MutS Homolog 3 Protein
  • Nuclear Proteins
  • EXO1 protein, human
  • Exodeoxyribonucleases
  • MSH2 protein, human
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein
  • DNA Repair Enzymes