Abstract 4595: The impact of CYP2A6 genetic polymorphisms on nicotine metabolism and lung cancer risk in two prospective cohorts of smokers

Abstract

Abstract Background. Cytochrome P450 2A6 (CYP2A6) is polymorphic and catalyzes the metabolism of nicotine and certain tobacco-specific carcinogens, including 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), thus may affect smoking behavior and contribute to substantial inter-individual variation in risk of smoking-related lung cancer. CYP2A6 genetic profiling coupled with biomarkers of tobacco constituents may enhance our understanding of the gene-environmental interaction on lung cancer risk and identify high-risk smokers for targeted preventive interventions. Methods. A nested case-control study including 513 incident lung cancers and an equal number of individually matched controls, all current smokers, was conducted within two population-based prospective cohorts with >80,000 Chinese men and women aged 45-74 years in Shanghai and Singapore. Quantified were 4 common allelic variants of CYP2A6 (*4, *7, *9 and rs1137115), urinary total nicotine, total cotinine (COT), total 3-hydroxy cotinine (3HC), and total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL, a NNK metabolite). Calculated were total nicotine equivalent (TNE = the sum of total nicotine, COT and 3HC), and the 3HC:COT ratio as a measure of CYP2A6 activity. Logistic regression method was used to calculate odd ratios and 95% confidence intervals for lung cancer associated CYP2A6 genotypes and urinary biomarkers. Results. The smoking-adjusted ORs (95% CIs) of lung cancer comparing the highest to lowest quartile of total nicotine, total COT, total 3HC, TNE, and total NNAL were 2.49 (1.72-3.62), 3.03 (2.35-5.41), 3.56 (2.35-5.41), 3.35 (2.25-5.00), and 2.43 (1.65-3.57), respectively (all Ps for trend < 0.001). All 4 individual mutant variants of CYP2A6 were associated with reduced 3HC:COT ratio (all Ps for trend < 0.05). When all 4 genotypes were combined to create a CYP2A6 index with 5 groups: G1 (most efficient) to G5 (least efficient), the 3HC:COT ratio for G1 was 4 times that of G5 with a strong dose-dependent genotype-phenotype relation (P trend < 0.001). Smokers with CYP2A6 G5 consumed significantly fewer cigarettes and excreted lower urinary TNE (P trend < 0.001). Compared with CYP2A6 G1, the multivariate-adjusted ORs (95% CIs) of lung cancer for G2, G3, G4 and G5 were 0.95 (0.64-1.42), 1.04 (0.67-1.63), 0.54 (0.34-0.86) and 0.69 (0.43-1.13), respectively, (P trend = 0.005). Furthermore, there was a suggestive interaction between CYP2A6 index and total NNAL on lung cancer risk (P interaction = 0.087). Conclusion. CYP2A6 genetic polymorphisms have a strong influence on cigarette consumption, nicotine uptake and metabolism. In addition to reduced carcinogen exposure, altered metabolism of the tobacco-specific carcinogen NNK may contribute to the reduced risk of lung cancer in smokers with low functional CYP2A6 genotypes. Grants: R01 CA129534, R01 CA144034, UM1 CA182876. Citation Format: Jian-Min Yuan, Heather H. Nelson, Lesley M. Butler, Steven G. Carmella, Renwei Wang, Jennifer Adams-Haduch, Stephen S. Hecht, Woon-Puay Koh, Yu-Tang Gao, Sharon E. Murphy. The impact of CYP2A6 genetic polymorphisms on nicotine metabolism and lung cancer risk in two prospective cohorts of smokers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4595. doi:10.1158/1538-7445.AM2015-4595