Wang Haijian, Tan Wen, Hao Bingtao, Miao Xiaoping, Zhou Gangqiao, He Fuchu, Lin Dongxin
Laboratory of Systems Biology, Beijing Institute of Radiation Medicine, and Chinese National Human Genome Center at Beijing, Beijing 100850, China.
Cancer Res. 2003 Nov 15;63(22):8057-61.
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.
细胞色素P450 2A13（CYP2A13）是一种主要在人类呼吸道中表达的酶，在烟草致癌物4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）的代谢活化中表现出高效性。CYP2A13基因中的C→T转换导致精氨酸257变为半胱氨酸的氨基酸替代，从而导致对NNK和其他底物的活性显著降低。在这项病例对照研究中，我们对724例肺癌患者和791例对照进行了该多态性的基因分型，以检验变异型CYP2A13可能影响与吸烟相关的肺癌风险这一假设。另一种参与烟草亚硝胺代谢活化的酶CYP2A6中的基因缺失多态性（CYP2A6*4）也作为对照进行了分析。我们发现，与CC基因型相比，变异型CYP2A13基因型（CT + TT）与肺腺癌风险大幅降低相关[比值比（OR），0.41；95%置信区间（CI），0.23 - 0.71]，但与鳞状细胞癌无关（OR，0.86；95% CI，0.57 - 1.29）或其他类型的肺癌无关（OR，0.58；95% CI，0.32 - 1.09）。分层分析表明，与变异型CYP2A13基因型相关的肺腺癌风险降低仅限于吸烟者，尤其是轻度吸烟者（OR，0.23；95% CI，0.08 - 0.68），而非不吸烟者或重度吸烟者。未观察到CYP2A6基因型与肺癌风险之间的关联。我们的结果首次证明变异型CYP2A13等位基因与肺腺癌风险降低相关，提示NNK - CYP2A13相互作用作为癌症致病因素的作用。
