McKay James D, Hashibe Mia, Hung Rayjean J, Wakefield Jon, Gaborieau Valerie, Szeszenia-Dabrowska Neonila, Zaridze David, Lissowska Jolanta, Rudnai Peter, Fabianova Eleonora, Mates Dana, Foretova Lenka, Janout Vladimir, Bencko Vladimir, Chabrier Amelie, Hall Janet, Boffetta Paolo, Canzian Federico, Brennan Paul
Association for International Cancer Research, 150 cours Albert Thomas, Lyon Cedex 08, France.
Cancer Epidemiol Biomarkers Prev. 2008 Jan;17(1):141-7. doi: 10.1158/1055-9965.EPI-07-0553.
Tobacco smoke contains an extensive cocktail of highly carcinogenic chemicals. Individuals with a slower elimination rate of the chemicals in tobacco smoke may have increased exposure to their carcinogenic properties compared with those with a faster rate. Polymorphisms that alter the function of the genes involved in the activation or the detoxification of the chemical carcinogens in tobacco smoke can potentially influence an individual's risk of developing a tobacco-related cancer. To test this hypothesis, we have genotyped polymorphisms in 16 genes involved in metabolism of chemical carcinogens in a Central and Eastern European case-control study comprising 2,250 lung cases, 811 upper aerodigestive cancer (UADT) cases, and 2,704 controls. The N-acetyltransferase (NAT) genes were the most implicated in risk, with the NAT110 haplotype showing an inverse association in lung cancer, in both heterozygote carriers [odds ratio (OR), 0.81; 95% confidence interval (95% CI), 0.70-0.93] and homozygote carriers (OR, 0.70; 95% CI, 0.48-1.01), suggesting a genotype dose response (P < 0.001). In UADT cancer, a similar inverse association was noted in NAT110 although only in heterozygotes (OR, 0.78; 95%CI, 0.65-0.95). In NAT2, when considering the individuals inferred acetylator phenotypes based on their NAT2 diplotype, "slow" acetylators compared with intermediate or fast acetylators showed no association with risk. None of the other 14 genes provided robust evidence of an association for either lung or UADT cancer. We therefore conclude that, of the genetic variation studied, NAT1 gene was the most likely candidate to influence the risk of developing a tobacco-related cancer.
烟草烟雾中含有大量高度致癌的化学物质混合物。与那些代谢速率较快的人相比，烟草烟雾中化学物质消除速率较慢的个体可能会更多地接触到其致癌特性。改变参与烟草烟雾中化学致癌物激活或解毒的基因功能的多态性可能会潜在地影响个体患烟草相关癌症的风险。为了验证这一假设，我们在一项中东欧病例对照研究中对参与化学致癌物代谢的16个基因中的多态性进行了基因分型，该研究包括2250例肺癌病例、811例上呼吸消化道癌（UADT）病例和2704例对照。N - 乙酰转移酶（NAT）基因与风险关联最为密切，NAT110单倍型在肺癌中显示出负相关，杂合子携带者[比值比（OR），0.81；95%置信区间（95%CI），0.70 - 0.93]和纯合子携带者（OR，0.70；95%CI，0.48 - 1.01）均如此，提示存在基因型剂量反应（P < 0.001）。在UADT癌症中，NAT110也有类似的负相关，不过仅在杂合子中（OR，0.78；95%CI，0.65 - 0.95）。在NAT2方面，根据个体的NAT2双倍型推断出乙酰化表型后，“慢”乙酰化者与中间型或快乙酰化者相比，未显示出与风险的关联。其他14个基因中，没有一个能为肺癌或UADT癌症的关联提供有力证据。因此，我们得出结论，在所研究的基因变异中，NAT1基因最有可能是影响患烟草相关癌症风险的候选基因。
