The Role of Phase II Detoxification Genes Towards Modulating Risk for Lung Cancer and its Association with Clinical Outcomes

Abstract

Background: Lung cancer is the leading cause of cancer mortality globally, and the key risk factors are smoking and occupational exposure. The presence of polymorphic genes affecting the levels of metabolic activation and carcinogen detoxification influences lung cancer susceptibility. Objectives To evaluate the role of single nucleotide polymorphic variants of Phase II detoxification genes NQO1 (rs1800566), SULT1A1 (rs9282861), EPHX1 (rs1051740, rs2234922), NAT2 (rs1799929, rs1799930, rs1799931, rs1208), MTHFR (rs1801133, rs1801131) and GSTP1 (rs1695). Methodology Genotyping of genomic DNA was carried out using PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) for each polymorphic site under study. Total number of subjects genotyped in case of NQO1, SULT1A1, EPHX1, and NAT2 were 1100 (550 cases, 550 controls); in MTHFR were 253 cases and in case of GSTP1 682 cases, respectively. Following this association study, logistic regression was used to get the adjusted odds ratio and significance. To find the possible connection between interacting SNP-SNP and gene-gene interactions, data mining analysis was performed that included both Multi-dimensionality reduction (MDR) and Classification and Regression tree (CART) analysis. Overall survival analysis was carried out using Kaplan-Meier survival analysis and Cox-regression analysis, which yielded the adjusted hazards ratio. Results The TT genotype for NQO1 609CgtT polymorphism exhibited a good association with LC risk in regards of clinical-pathological parameters. A 3.5 fold higher odds in subjects with stageIII (p=0.0006),5 fold higher probability of lymph-node invasion(p=0.007) and an odds of less than one in case of metastasis(p=0.0028). Furthermore, 473 subjects were analyzed in regards of overall survival, wherein the TT genotype exhibited a better OS than CC genotype (9.43vs.8.13months). Whereas,