Abstract 4595: The impact of CYP2A6 genetic polymorphisms on nicotine metabolism and lung cancer risk in two prospective cohorts of smokers
Authors: Yuan Jian-Min , Nelson Heather H. , Butler Lesley M. , Carmella Steven G. , Wang Renwei , Adams-Haduch Jennifer , Hecht Stephen S. , Koh Woon-Puay , Gao Yu-Tang , Murphy Sharon E. 
Published: August 2015

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 &gt;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 &lt; 0.001). All 4 individual mutant variants of CYP2A6 were associated with reduced 3HC:COT ratio (all Ps for trend &lt; 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 &lt; 0.001). Smokers with CYP2A6 G5 consumed significantly fewer cigarettes and excreted lower urinary TNE (P trend &lt; 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