Schneider Joachim, Bernges Ulrike, Philipp Monika, Woitowitz Hans-Joachim
Institut und Poliklinik für Arbeits- und Sozialmedizin der Justus-Liebig Universität, Giessen, Germany.
Cancer Genomics Proteomics. 2004 Mar-Apr;1(2):189-198. Epub 2004 Mar 1.
The impact of genetic polymorphisms in CYP1A1 or CYP1B1 on susceptibility to lung cancer has received particular attention since these enzymes play a central role in the activation of major classes of tobacco carcinogens. Several polymorphisms in the CYP1A1 locus have been identified and their genotypes appear to exhibit population frequencies that depend on ethnicity. In the current German study, we investigated the role of CYP1A1 and CYP1B1 polymorphisms as a genetic modifier of risk for individuals with lung cancers as susceptible genotypes, especially in relation to tobacco smoking.
Three polymorphisms, the CYP1A1 T6235C (CYP1A1 MspI), the CYP1A1 A4889G-position (CYP1A1 iva) as well as the CYP1B1 codon 432 polymorphism were determined by real-time PCR analysis in 446 lung cancer patients and in 622 controls.
The observed allele frequencies in the population were within the range described for Caucasians. Multivariate analyses of lung cancer patients, who carried at least one mutant variant allele of CYP1A1 T6235C (OR=1.06; 95%-CI: 0.7-1.6), CYP1A1 A4889G (OR=1.09; 95%-CI: 0.63-1.88) or CYP1B1 Val432Leu (OR=1.01 CI: 0.73-1.39) did not show any elevated risks. When analysed by histology, no individual subtype of lung cancer was significantly associated with the polymorphisms. Lung cancer risk rose significantly with higher cumulative cigarette consumption. Stratified analysis between tobacco smoking and variant genotypes revealed, for heavy smokers (>60 pack-years), increasing risks with the presence of at least one copy of the CYP1A1 T6235C variant allele OR=27.74 (95%-CI: 4.34-177.25), the CYP1A1 A4889G position OR=33.23 (95%-CI: 3.11-354.99) and the CYP1B1 OR=418.70 (95%-CI: 45.45-3856.89). By analysing the interaction between tobacco smoking and the genotypes, the combination of smoking and having the susceptible genotypes did not show a joint effect.
In this study polymorphism of the CYP1A1 T6235C- or A4889G-position as well as CYP1B1-codon 432-polymorphisms had no relevant modifying effect on lung cancer risk and cumulative smoking dose.
由于CYP1A1和CYP1B1酶在主要烟草致癌物的激活过程中起核心作用，因此这些酶的基因多态性对肺癌易感性的影响受到了特别关注。已在CYP1A1基因座中鉴定出几种多态性，其基因型的群体频率似乎取决于种族。在当前的德国研究中，我们调查了CYP1A1和CYP1B1多态性作为肺癌患者易感性基因型风险的遗传修饰因子的作用，特别是与吸烟的关系。
通过实时PCR分析，对446例肺癌患者和622例对照者检测了三种多态性，即CYP1A1 T6235C（CYP1A1 MspI）、CYP1A1 A4889G位点（CYP1A1 iva）以及CYP1B1密码子432多态性。
人群中观察到的等位基因频率在白种人描述的范围内。对携带CYP1A1 T6235C至少一个突变变异等位基因（OR = 1.06；95%可信区间：0.7 - 1.6）、CYP1A1 A4889G（OR = 1.09；95%可信区间：0.63 - 1.88）或CYP1B1 Val432Leu（OR = 1.01，可信区间：0.73 - 1.39）的肺癌患者进行多变量分析，未显示任何风险升高。按组织学分析时，肺癌的任何个体亚型均与多态性无显著关联。肺癌风险随累积吸烟量增加而显著上升。吸烟与变异基因型之间的分层分析显示，对于重度吸烟者（>60包年），存在至少一个CYP1A1 T6235C变异等位基因拷贝时风险增加，OR = 27.74（95%可信区间：4.34 - 177.25），CYP1A1 A4889G位点OR = 33.23（95%可信区间：3.11 - 354.99），CYP1B1 OR = 418.70（95%可信区间：45.45 - 3856.89）。通过分析吸烟与基因型之间的相互作用，吸烟与具有易感基因型的组合未显示联合效应。
在本研究中，CYP1A1 T6235C或A4889G位点以及CYP1B1密码子432多态性对肺癌风险和累积吸烟剂量无相关修饰作用。
