Substantial reduction in risk of lung adenocarcinoma associated with genetic polymorphism in CYP2A13, the most active cytochrome P450 for the metabolic activation of tobacco-specific carcinogen NNK.
Cytochrome P450 2A13 (CYP2A13), an enzyme expressed predominantly in the human respiratory tract, exhibits high efficiency in the metabolic activation of tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). A C-->T transition in the CYP2A13 gene causes Arg257Cys amino acid substitution and, thus, results in a significantly reduced activity toward NNK and other substrates. In this case-control study, we genotyped 724 patients with lung cancer and 791 controls for this polymorphism to examine the hypothesis that the variant CYP2A13 may have impact on risk of lung cancer in relation to tobacco smoking. A gene deletion polymorphism (CYP2A6*4) in CYP2A6, another enzyme involved in the metabolic activation of tobacco nitrosamines, was also analyzed as a comparison. We found that, compared with the CC genotype, the variant CYP2A13 genotype (CT + TT) was associated with substantially reduced risk for lung adenocarcinoma [odds ratio (OR), 0.41; 95% confidence interval (CI), 0.23-0.71], but not squamous cell carcinoma (OR, 0.86; 95% CI, 0.57-1.29) or other types of lung cancer (OR, 0.58; 95% CI, 0.32-1.09). Stratification analysis shows that the reduced risk of lung adenocarcinoma related to the variant CYP2A13 genotype was limited to smokers, especially light smokers (OR, 0.23; 95% CI, 0.08-0.68) but not nonsmokers or heavy smokers. No association was observed between CYP2A6 genotype and risk of lung cancer. Our results demonstrate for the first time that the variant CYP2A13 allele is associated with reduced risk of lung adenocarcinoma, suggesting the role of NNK-CYP2A13 interaction as a causative factor for the cancer.
Wang
Haijian
H
Laboratory of Systems Biology, Beijing Institute of Radiation Medicine, and Chinese National Human Genome Center at Beijing, Beijing 100850, China.
Tan
Wen
W
Hao
Bingtao
B
Miao
Xiaoping
X
Zhou
Gangqiao
G
He
Fuchu
F
Lin
Dongxin
D
D000230:Adenocarcinoma / Q000201:enzymology / Q000209:etiology / Q000235:genetics*; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000209:etiology / Q000235:genetics; D016022:Case-Control Studies; D065637:Cytochrome P-450 CYP2A6; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D009602:Nitrosamines / Q000493:pharmacokinetics* / Q000633:toxicity; D011110:Polymorphism, Genetic; D012907:Smoking / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism
D002273:Carcinogens; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C414206:CYP2A13 protein, human; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6