Le Marchand L, Sivaraman L, Pierce L, Seifried A, Lum A, Wilkens L R, Lau A F
Etiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu 96813, USA.
Cancer Res. 1998 Nov 1;58(21):4858-63.
The dramatic shift in the pathological presentation of lung cancer [the proportional decrease in squamous cell carcinoma (SCC) and increase in adenocarcinoma (AC)] observed in the United States after the 1950s may have taken place as the result of the reduction in polycyclic aromatic hydrocarbons (PAHs) and the increase in N-nitrosamines in inhaled smoke from filtered low-yield cigarettes. The predominant mutation patterns of these tumors also suggest differences in their etiology. We tested the hypothesis that genetic susceptibility to PAHs, as determined by polymorphisms in CYP1A1 and GSTM1, predominantly causes lung SCCs, and susceptibility to nitrosamines, as determined by polymorphisms in CYP2E1, predominantly causes lung ACs. CYP1A1 and GSTM1 play a major role in the metabolic activation and detoxification of PAHs, respectively, and CYP2E1 plays a major role in the metabolic activation of nitrosamines. We conducted a population-based case-control study among 341 incident lung cancer cases and 456 controls of Caucasian, Japanese, or Hawaiian origin. In-person interviews collected detailed information on lifestyle risk factors, and DNA extracted from peripheral leukocytes was used in PCR-based genotyping assays. Logistic regression analyses were used to compute odds ratios and 95% confidence intervals (CIs) for each cell type, adjusting for smoking and dietary variables. The presence of at least one copy of the CYP1A1 MspI variant allele was found to be associated with a 2.4-fold (95% CI, 1.2-4.7) increase in the risk of SCC when this gene was considered singly and a 3.1-fold (95% CI, 1.2-7.9) increase in the risk of SCC when combined with a GSTM1 deletion. No significant association was found between MspI and all lung cancers or other cell types or with the CYP1A1 exon 7 polymorphism. In contrast, the CYP2E1 RsaI and DraI polymorphisms were not clearly related to SCC risk, but these homozygous variant genotypes were associated with a 10-fold (95% CI, 0.0-0.5) decrease in the risk of overall lung cancer (RsaI variant) and AC (DraI variant) compared to the homozygous wild-type genotypes. Inverse associations with these two closely linked CYP2E1 polymorphisms were also suggested for small cell carcinoma. In agreement with past experimental and epidemiological data, the associations found in this study between CYP1A1 and lung SCC and between CYP2E1 and lung AC suggest a certain specificity of tobacco smoke PAHs for lung SCC and tobacco-specific nitrosamines for lung ACs.
20世纪50年代后在美国观察到的肺癌病理表现的显著变化[鳞状细胞癌（SCC）比例下降，腺癌（AC）比例上升]，可能是由于过滤式低焦油香烟吸入烟雾中多环芳烃（PAHs）减少以及N-亚硝胺增加所致。这些肿瘤的主要突变模式也表明其病因存在差异。我们检验了以下假设：由CYP1A1和GSTM1基因多态性决定的对PAHs的遗传易感性主要导致肺SCC，由CYP2E1基因多态性决定的对亚硝胺的易感性主要导致肺AC。CYP1A1和GSTM1分别在PAHs的代谢活化和解毒中起主要作用，而CYP2E1在亚硝胺的代谢活化中起主要作用。我们在341例新发肺癌病例和456例白种人、日本人或夏威夷人后裔的对照中进行了一项基于人群的病例对照研究。通过面对面访谈收集了生活方式危险因素的详细信息，并将从外周血白细胞中提取的DNA用于基于PCR的基因分型检测。采用逻辑回归分析计算每种细胞类型的比值比和95%置信区间（CIs），并对吸烟和饮食变量进行了校正。当单独考虑该基因时，发现CYP1A1 MspI变异等位基因至少有一个拷贝与SCC风险增加2.4倍（95%CI，1.2 - 4.7）相关，与GSTM1缺失联合时，SCC风险增加3.1倍（95%CI，1.2 - 7.9）。未发现MspI与所有肺癌或其他细胞类型或CYP1A1外显子7多态性之间存在显著关联。相比之下，CYP2E1 RsaI和DraI多态性与SCC风险无明显关联，但与纯合野生型基因型相比，这些纯合变异基因型与总体肺癌（RsaI变异）和AC（DraI变异）风险降低10倍（95%CI，0.0 - 0.5）相关。对于小细胞癌，也提示与这两个紧密连锁的CYP2E1多态性存在负相关。与过去的实验和流行病学数据一致，本研究中发现的CYP1A1与肺SCC以及CYP2E1与肺AC之间的关联表明，烟草烟雾中的PAHs对肺SCC具有一定特异性，而烟草特异性亚硝胺对肺AC具有一定特异性。
