Studies on genetic polymorphism in nucleotide excision repair genes in relation to lung cancer patients

Abstract

DNA repair genes safeguard the genomic integrity from the exogenous as well as endogenous assaults. Molecular alterations in the repair pathway genes may lead to improper repair and ultimately carcinogenesis. Objectives To evaluate the role of single nucleotide polymorphic variants of Nucleotide Excision Repair (NER) genes i.e. XPC (Lys939Gln, Ala499Val), XPA (A23G, G709A), XPD (Lys939Gln, Asp312Asn, Arg156Arg), XPG (Phe670Leu, Asp1104His) and XPF (673CgtT, 11985AgtG and Arg415Gln) with lung cancer susceptibility, overall survival and clinical response. Gene-gene and gene-environment interaction were also assessed to understand their association with lung cancer. 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 for each polymorphic variant was 740 (370 cases, 370 controls). Following this association analysis was carried out using logistic regression to obtain adjusted odds ratio and significance. Data mining analysis was performed including both Multi-dimensionality reduction (MDR) and Classification and Regression tree (CART) analysis to find the possible interaction between interacting SNP-SNP and gene-gene. Overall survival analysis for 311 cases was performed using Kaplan Meier survival analysis and Cox-regression analysis which gave adjusted hazards ratio. Multivariate logistic regression analysis for 202 samples was also conducted to evaluate association of different polymorphic variants with clinical response. Results XPC Lys939Gln possessed risk for lung cancer (OR: 2.30; p=0.0007). Lys939Gln polymorphism also showed higher risk for all sub-groups of lung cancer. For subjects with mutant genotype (CC) had a 4 and 3-fold increased risk for ADCC (plt0.0001) and SQCC (p=0.009).