Single Nucleotide Polymorphism in Mismatch Repair Pathway Genes and its Computational Analysis in Lung Cancer Patients

Abstract

Background: Lung cancer is the leading, cause of cancer mortality globally, and the critical risk factors are smoking and occupational exposure. Molecular alterations in the repair pathway genes may lead to improper repair and, ultimately, carcinogenesis. Objective: To evaluate the role of single nucleotide polymorphic variants of DNA mismatch repair (MMR) genes i.e. MLH1 (rs1800734), MSH3 (rs26279), MSH6 (rs3136228, rs1800932, rs1042821) and MSH2 (rs63749993, rs2303425, rs2303426, rs4987188, rs2303428, and rs17217772) towards lung cancer susceptibility. Methodology: The study was designed to find out any association between genetic polymorphism of mismatch repair pathway genes and risk of developing lung cancer. This study recruited 500 lung cancer patients from the Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), and 500 healthy controls. These cancer patients were further subdivided in to smaller subgroups based on histology of lung cancer, gender, smoking status (Yes/No and Heavy smokers/ Light smokers). Genomic DNA from lung cancer subjects was genotyped using PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) for each polymorphic site under study. Logistic regression was used to analyze subjects to determine any association towards development of lung cancer. Classification and Regression tree (CART) analysis was carried to understand SNP-SNP (single nucleotide polymorphism) interaction. Overall survival analysis was carried out using Kaplan-Meier survival analysis and Cox-regression analysis. Toxicity associated with different chemotherapeutic regimen was also evaluated. Further different computational tools were used to analyze the nsSNPs to evaluate their effect on structure and stability of the protein. Results: For MLH1 polymorphism, reduced risk of developing Adenocarcinoma (ADCC) in patients harboring variant (p= 0.0007) and combined type genotype (p=0.008) was reported.