Harth Volker, Schafer Martin, Abel Josef, Maintz Laura, Neuhaus Thomas, Besuden Mette, Primke Robert, Wilkesmann Anja, Thier Ricarda, Vetter Hans, Ko Yon-Dschun, Bruning Thomas, Bolt Hermann M, Ickstadt Katja
BGFA-Research Institute of Occupational Medicine, German Social Accident Insurance, University of Bochum, Bochum, Germany.
J Toxicol Environ Health A. 2008;71(13-14):887-97. doi: 10.1080/15287390801988160.
Tobacco smoking, alcohol drinking, and occupational exposures to polycyclic aromatic hydrocarbons are the major proven risk factors for human head and neck squamous-cell cancer (HNSCC). Major research focus on gene-environment interactions concerning HNSCC has been on genes encoding enzymes of metabolism for tobacco smoke constituents and repair enzymes. To investigate the role of genetically determined individual predispositions in enzymes of xenobiotic metabolism and in repair enzymes under the exogenous risk factor tobacco smoke in the carcinogenesis of HNSCC, we conducted a case-control study on 312 cases and 300 noncancer controls. We focused on the impact of 22 sequence variations in CYP1A1, CYP1B1, CYP2E1, ERCC2/XPD, GSTM1, GSTP1, GSTT1, NAT2, NQO1, and XRCC1. To assess relevant main and interactive effects of polymorphic genes on the susceptibility to HNSCC we used statistical models such as logic regression and a Bayesian version of logic regression. In subgroup analysis of nonsmokers, main effects in ERCC2 (Lys751Gln) C/C genotype and combined ERCC2 (Arg156Arg) C/A and A/A genotypes were predominant. When stratifying for smokers, the data revealed main effects on combined CYP1B1 (Leu432Val) C/G and G/G genotypes, followed by CYP1B1 (Leu432Val) G/G genotype and CYP2E1 (-70G>T) G/T genotype. When fitting logistic regression models including relevant main effects and interactions in smokers, we found relevant associations of CYP1B1 (Leu432Val) C/G genotype and CYP2E1 (-70G>T) G/T genotype (OR, 10.84; 95% CI, 1.64-71.53) as well as CYP1B1 (Leu432Val) G/G genotype and GSTM1 null/null genotype (OR, 11.79; 95% CI, 2.18-63.77) with HNSCC. The findings underline the relevance of genotypes of polymorphic CYP1B1 combined with exposures to tobacco smoke.
吸烟、饮酒以及职业性接触多环芳烃是已证实的人类头颈部鳞状细胞癌（HNSCC）的主要危险因素。关于HNSCC的基因-环境相互作用的主要研究重点一直是编码烟草烟雾成分代谢酶和修复酶的基因。为了研究在烟草烟雾这种外源性危险因素作用下，遗传决定的个体易感性在异源物代谢酶和修复酶中对HNSCC致癌作用的影响，我们对312例病例和300例非癌症对照进行了一项病例对照研究。我们重点关注了CYP1A1、CYP1B1、CYP2E1、ERCC2/XPD、GSTM1、GSTP1、GSTT1、NAT2、NQO1和XRCC1基因中的22个序列变异的影响。为了评估多态性基因对HNSCC易感性的相关主要效应和交互效应，我们使用了逻辑回归和贝叶斯逻辑回归等统计模型。在不吸烟者的亚组分析中，ERCC2（Lys751Gln）C/C基因型以及ERCC2（Arg156Arg）C/A和A/A基因型的组合的主要效应占主导地位。在按吸烟者分层时，数据显示对CYP1B1（Leu432Val）C/G和G/G基因型组合有主要效应，其次是CYP1B1（Leu432Val）G/G基因型和CYP2E1（-70G>T）G/T基因型。当拟合包含吸烟者相关主要效应和交互作用的逻辑回归模型时，我们发现CYP1B1（Leu432Val）C/G基因型和CYP2E1（-70G>T）G/T基因型（比值比，10.84；95%置信区间，1.64 - 71.53）以及CYP1B1（Leu432Val）G/G基因型和GSTM1无效/无效基因型（比值比，11.79；95%置信区间，2.18 - 63.77）与HNSCC相关。这些发现强调了多态性CYP1B1基因型与接触烟草烟雾的相关性。
