细胞色素P450基因多态性与肺癌易感性的相关性分析

Combined effects of genetic polymorphisms in cytochrome P450s and GSTM1 on lung cancer susceptibility

目的探讨代谢活化酶细胞色素 P4501A1(CYP1A1)、2D6(CYP2D6)、2E1(CYP2E1)和代谢解毒酶谷胱甘肽硫转移酶(GSTM1)与肺癌易感性的关系。方法采用 PCR、PCR-RFLP 技术检测原发性肺癌组(279例)及对照组(684例)的 CYP1A1、CYP2D6、CYP2E1、GSTM1代谢酶基因型,对不同基因型在两组分布频率的差异进行 OR 值的统计分析。结果 CYP1A1突变等位基因(m)、GSTM1功能缺失型(-)分别可使患肺癌的危险性增加1.64(OR=1.64,95%CI 为1.21～2.22,P=0.001)和1.58倍(OR=1.58,95%CI 为1.19～2.11,P=0.002)。其中 CYP1A1与肺鳞癌,小细胞癌,GSTM1与肺鳞癌及肺腺癌明显相关(均 P<0.05)。同时携带 GSTM1(-)和 CYP1A1(m)可使患肺癌的危险性明显增加(OR=2.75,95%CI 为1.73～4.39,P=0.000)。在重度吸烟人群携带GSTM1(-)、CYP1A1(m)、CYP2D6(w)或 CYP2E1A 基因型均可使患肺癌的危险性显著增加5.71～11.67倍(P=0.000)。结论携带 GSTM1(-)及 CYP1A1(m)等位基因型者患肺癌的危险性上升,二者有协同作用。在重度吸烟人群,CYP 及 GSTM1的检测有利于发现肺癌的高危人群。

Objective To investigate the relationship between the gene polymorphism of metabolizing enzymes and the genetic susceptibility to lung cancer as well as to study the synergistic effects between smoking and the genes. Methods Peripheral blood samples were collected from 279 patients with primary lung cancer and 684 age-, nationality-, and native place-matched controls, including patients with benign diseases and healthy volunteers. PCR-RELP was used to detect the distribution of CYP1A1, 2D6, 2E1, and GSTM1 genotypes. The correlation of these genes with the sensibility to lung cancer was analyzed. Results The CYP1 A1 variant allele frequency of the lung cancer group was 67. 4% , significantly higher than that of the control group （ 55.7% , P = 0. 001 ） . GSTMl-null genotype was found to be associated with lung cancer（ OR = 1.58, P = 0. 002）. The risk of lung cancer in the individuals carrying GSTMI-null genotype and CYP1A1 （w/m, m/m） genotype was 2. 75 times that of the individuals not carrying these genotypes （ P 〈 0. 01 ）. There were no significant differences in the frequencies of CYP2D6 and CYP2E1 genotypes between these two groups. In the heavy smokers GSTMI-null, CYP1A1, CYP2D6, and CYP2E1 genotypes increased the risk of lung cancer by 5.71 -11.67 times （P=0.000）. Conclusion The individuals who carry GSTMI-null genotype and CYP1A1 （m） genotype have an increase risk of lung cancer. The combined effect of I phase metabolizing enzymes and II phase metabolizing enzymes is observed. In heavy smokers the polymorphism of GSTM1 and CYPs affects the susceptibility to lung cancer.