Relevance of genetic polymorphisms in tobacco-related detoxifying enzymes in non-small cell lung carcinoma susceptibility

Abstract

BackgroundTobacco smoking plays a role in the onset and development of non-small cell lung cancer (NSCLC). Biotransformation and detoxification of tobacco smoke carcinogens are brought about by xenobiotic-metabolizing enzymes (XME). Germline mutations in CYP1B1 (Ala119Ser) and GSTT1 (+/−) have been known to affect the functionality of these enzymes, thereby modifying their effect; amino acid substitution and complete gene deletion abolish enzyme activity. CYP1B1 (Ala119Ser) and GSTT1 (+/–) genotypic interactions and gene-smoking inteaction associated risk of NSCLC information is not documented in the literature. ObjectiveThe role of gene-gene and gene-smoking interaction with the clinicopathological parameters to estimate the risk of NSCLC among the North Indian population. MethodsCYP1B1 and GSTT1 genotypes were determined by the PCR-RFLP in 158 cases of NSCLC and 155 controls; demographical parameters and clinicopathological characteristics were recorded. ResultsGSTT1 (−/−) genotype demonstrated a four-fold risk of NSCLC and was significantly associated with squamous cell lung carcinoma (OR: 3.35). Synergistic interaction of CYP1B1 (Variant) and GSTT1 (−/−) enhanced the risk of NSCLC by 6.5 fold. CYP1B1 mutant genotypes in tobacco smokers showed a 3.5 fold risk, which was significantly (p = 0.02) higher than the non-smokers (OR: 1.67, p = 0.38). NSCLC risk with GSTT1 mutant genotype showed a similar trend of risk in both smokers (OR: 4.1) and non-smokers (OR: 3.8). ConclusionThe effect of CYP1B1 mutant appears to be a risk modifier in tobacco smokers, whereas deletions in GSTT1 (−/−) increases the risk of NSCLC in both smokers and non-smokers. A marked synergistic risk was evident when both mutations were present.