Genetic Polymorphisms In Carcinogen-Metabolizing Enzymes MPO, GSTM1, UGT1A7 And MEH And Susceptibility To Lung Cancer

Tobacco smoke and environmental pollution, which are believed to be associated with lung cancer, hold a large number of carcinogens. These carcinogens require metabolic activation to damage DNA and induce genotoxicity and carcinogenecity. Therefore, functional polymorphisms in genes encoding enzymes involved in activation or detoxification of carcinogens have been investigated as a possible genetic basis for interindividual variability in susceptibility to lung carcinogenesis. In the present study, we assessed the role of genetic polymorphisms in carcinogen-metabolizing enzymes, myeloperoxidase (MPO), glutathione S-transferase Ml (GSTM1), UDP-glucuronosyl-transferase (UGT1A7) and microsomal expoxide hydrolase (MEH) in risk of lung cancer. Genotypes of MPO, GSTM1, UGT1A7 and MEH were determined by PCR-SSCP, multiplex-PCR, PCR-DHPLC, and PCR-RFLP, respectively, in 314 patients with lung cancer and 320 frequency-matched controls. The associations between genotypes and haplotypes and risk of lung cancer were estimated by odds ratios (ORs) and their 95% confidence intervals (CIs) calculated by unconditional logistic regression.It was found that subjects with the MPO -463GG genotype were at 2-fold increased risk for squamous cell carcinoma (SCC) of the lung (OR, 2.35; 95% CI 1.40-3.94) compared with those with at least one -463A variant allele. Stratified analysis suggested an interaction between heavy smokers (≥ 26 pack-years) and the MPO-463GG genotype. The adjusted OR of lung SCC for those having MPO -463GG genotype and smoked ≥ 26 pack-years was 20.50 compared to 6.22 for those smoked ≥ 26 pack-years but having at least one variant A allele (P = 0.023, test for homogeneity). However, this effect of the MPO polymorphism was not observed in lung adenocarcinoma. Polymorphic UGT1A 7 was also associated with risk of lung cancer. It was observed that subjects having the UGT1A7*3/*1 genotype were at 1.80-fold (95% CI 1.03-3.12) increased risk for lung adenocarcinoma compared with those having the UGT1A7*1/*1 genotype, In addition, a moderated risk of lung adenocarcinoma (OR 1.59, 95% CI 0.96-2.63) was also associated with the UGT1A7*3 genotype. No association was found between the UGT1A7 polymorphism and SCC of the lung in this study. Similar results were obtained for MEH. Compared with subjects having the 113His/His genotype, those having the 113Tyr/Tyr genotype had an OR of 1.87 (95% CI 1.18-2.95) for lung adenocarcinoma and 1.55 (95% CI 0.96-2.51) for lung SCC. Furthermore, the increased risk of lung SCC related to 113Tyr/Tyr genotype was more pronounced in smokers and younger subjects. As the haplotypes were concerned, MEH*3 haplotype confered a 1.61-fold increased risk for lung SCC compared with the MEH*1 haplotype (OR, 1.61; 95% CI 1.06-2.44). No association between GSTM1 polymorphism and lung cancer risk was found in this study.These data support the hypothesis that sequence variations in genes encoding carcinogen-metabolizing enzymes may be genetic determinant for the development of lung cancer.