Abstract 4149: Genetic variation in CYP2A6, a nicotine/nitrosamine metabolism enzyme, influences lung cancer risk in two independent case-control studies of African American smokers
Authors: Wassenaar Catherine A. , Ye Yuanqing , Cai Qiuyin , Aldrich Melinda , Knight Joanne , Spitz Margaret R. , Wu Xifeng , Blot William J. , Tyndale Rachel F. 
Published: May 2015

Abstract
We investigated the association of CYP2A6 genotype with lung cancer risk among African American smokers to further our understanding of cancer susceptibility within this high-risk population. CYP2A6 gene variants are hypothesized to modify lung cancer risk among cigarette smokers by influencing smoking amount, through altered nicotine inactivation, and/or by influencing the bioactivation of carcinogenic tobacco-specific nitrosamines.
Participants were African American smokers drawn from two independent lung cancer case-control studies: a study nested within the Southern Community Cohort Study, Vanderbilt University, Nashville, TN with 1-2 controls matched to each incident lung cancer case by age, sex and recruitment site (SCCS: n = 494), and a case-control study from the University of Texas MD Anderson Cancer Center, Houston, TX with controls frequency matched to cases by smoking history in addition to age and sex (MDA: n = 407). Genotyping was performed for 12 CYP2A6 reduced/null activity alleles, and participants with genotypes associated with a 25% or more reduction in CYP2A6 activity were pooled together as reduced metabolizers. Lung cancer risk was estimated through logistic regression modeling, which permitted adjustments for smoking.
Compared to the CYP2A6 normal metabolism genotype group, the reduced metabolism group was associated with a significant reduction in lung cancer risk in SCCS, MDA, and in the pooled studies (SCCS: Odds ratio [OR] 0.62, 95% confidence interval [CI] 0.43-0.90; MDA: OR 0.66, 95% CI 0.44-0.98; Pooled: OR 0.64, 95% CI 0.49-0.84; ORs adjusted for age and sex). The association remained significant following additional adjustments for cigarettes/day and years of smoking (SCCS: OR 0.58, 95% CI 0.39-0.87; MDA: OR 0.66, 95% CI 0.44-0.99; Pooled: OR 0.62, 95% CI 0.47-0.83). Stratified analyses within the pooled studies revealed a consistent degree of CYP2A6 genetic risk across categories of cigarettes/day (≤10 cig/day: OR 0.65, 95% CI 0.43-0.98; 11-20 cig/day: OR 0.58, 95% CI 0.37-0.91; &gt;20 cig/day: OR 0.64, 95% CI 0.29-1.44) and further assessment of CYP2A6 genotype and lung cancer risk according to smoking duration and current/former smoking status is ongoing. We also noted a significant interaction between CYP2A6 genotype and sex on the risk for lung cancer (SCCS: P=.03; MDA: P=.03; Pooled: P=.003) with a greater effect in men. Additional analyses are underway to explore potential contributing factors to the observed interaction.
Genetic variation in CYP2A6 contributes to lung cancer risk among African American smokers, whereby CYP2A6 genotypes associated with reduced metabolic activity confer a lower risk of developing lung cancer.
Citation Format: Catherine A. Wassenaar, Yuanqing Ye, Qiuyin Cai, Melinda Aldrich, Joanne Knight, Margaret R. Spitz, Xifeng Wu, William J. Blot, Rachel F. Tyndale. Genetic variation in CYP2A6, a nicotine/nitrosamine metabolism enzyme, influences lung cancer risk in two independent case-control studies of African American smokers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4149. doi:10.1158/1538-7445.AM2014-4149