Chen C, Cook L S, Li X Y, Hallagan S, Madeleine M M, Daling J R, Weiss N S
Program in Cancer Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.
Cancer Epidemiol Biomarkers Prev. 1999 Apr;8(4 Pt 1):317-21.
The risks of anal and vulvar cancer are strongly related to cigarette smoking. Smokers are exposed to a substantial quantity of tobacco-specific nitrosamines, including 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). NNK is present in the mucus of the female genital tract. The enzyme debrisoquine 4-hydroxylase (CYP2D6) activates NNK and is present in foreskin kerotinocytes and cervical epithelial cells. A polymorphism for the gene CYP2D6 exists, and persons who possess alleles that are associated with reduced levels of CYP2D6 activity might be expected to be at a relatively lower risk of cancers arising from NNK exposure. To test this hypothesis, we conducted a case-control study to examine the association of CYP2D6 genotype and the incidence of anal and vulvar cancer among cigarette smokers in western Washington State. We tested for 14 alleles (*1-*12, *14, and *17) among cases (25 men and 43 women with anal cancer, 64 women with vulvar cancer) and controls (30 men and 110 women). Contrary to the hypothesis, cases were not less likely than controls to have one (43.9 versus 40.7%) or two (6.8 versus 4.3%) inactivating alleles (*3, *4, *5, *6, *7, *8, *11, or *12). There was a suggestion that, if anything, the combined anal and vulvar cancer risk increased (rather than decreased) with an increasing number of CYP2D6 inactivation alleles: odds ratio = 1.2, 95% confidence interval = 0.7-2.0 with one inactivating allele; odds ratio = 1.8, 95% confidence interval = 0.6-5.4 with two inactivating alleles. These results provide no support for the hypothesis that cigarette smokers who carry the CYP2D6 alleles that result in a low activity phenotype have a decreased risk of anogenital cancer.
肛管癌和外阴癌的风险与吸烟密切相关。吸烟者会接触到大量烟草特有的亚硝胺，包括4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）。NNK存在于女性生殖道的黏液中。异喹胍4-羟化酶（CYP2D6）可激活NNK，且存在于包皮角质形成细胞和宫颈上皮细胞中。CYP2D6基因存在多态性，拥有与CYP2D6活性水平降低相关等位基因的个体，可能因NNK暴露而患癌风险相对较低。为验证这一假设，我们开展了一项病例对照研究，以调查华盛顿州西部吸烟人群中CYP2D6基因型与肛管癌和外阴癌发病率之间的关联。我们对病例组（25名患肛管癌男性和43名患肛管癌女性、64名患外阴癌女性）和对照组（30名男性和110名女性）的14个等位基因（*1-*12、14和17）进行了检测。与假设相反，病例组携带一个（43.9%对40.7%）或两个（6.8%对4.3%）失活等位基因（*3、*4、*5、*6、*7、*8、11或12）的可能性并不低于对照组。有迹象表明，如果有什么不同的话，随着CYP2D6失活等位基因数量的增加，肛管癌和外阴癌的综合风险会升高（而非降低）：携带一个失活等位基因时，比值比=1.2，95%置信区间=0.7-2.0；携带两个失活等位基因时，比值比=1.8，95%置信区间=0.6-5.4。这些结果并不支持携带导致低活性表型的CYP2D6等位基因的吸烟者患肛门生殖器癌风险降低这一假设。
