Ishibe N, Hankinson S E, Colditz G A, Spiegelman D, Willett W C, Speizer F E, Kelsey K T, Hunter D J
Department of Epidemiology, Harvard School of Public Health, and Channing Laboratory, Boston, Massachusetts 02115, USA.
Cancer Res. 1998 Feb 15;58(4):667-71.
Environmental exposure to carcinogens may contribute to increasing breast cancer rates and geographic variation in breast cancer incidence in the United States. One class of chemicals that has received much attention are the polyaromatic hydrocarbons that are ubiquitous in the environment and occur in cigarette smoke. The cytochrome P450 1A1 (CYP1A1) gene codes for an enzyme that contributes to aryl hydrocarbon hydroxylase activity, which is involved in the metabolism of polyaromatic hydrocarbons. Genotypic variants of CYP1A1 have been associated with increased aryl hydrocarbon hydroxylase activity, and some epidemiological studies suggest that women with the variant genotype(s) are at increased risk for breast cancer. We prospectively evaluated the associations between the CYP1A1 polymorphisms and breast cancer risk, as well as the potential modification of these associations by cigarette smoking, in a case-control study nested within the Nurses' Health Study. We analyzed the T-->C transition at nucleotide 6235 (MspI) and the A-->G transition at nucleotide 4889 (exon 7) in CYP1A1 by PCR-RFLP assays among 466 incident breast cancer cases and 466 matched controls. Relative risks (RRs) and 95% confidence intervals (CIs) were used to quantify the risk of breast cancer among subjects who had at least one variant allele relative to subjects who were homozygous for the wild-type allele, using conditional logistic regression. No overall increase in breast cancer risk with the variant CYP1A1 genotypes was apparent (RR(MspI), 1.05; 95% CI, 0.74-1.50 and RR(exon7), 0.88; 95% CI, 0.58-1.33). However, a suggestive increase in breast cancer risk was observed among women who had commenced smoking before the age of 18 and had the CYP1A1-MspI variant genotype compared to nonsmokers who were homozygous wild type for the polymorphism (RR, 5.65; 95% CI, 1.50-21.3; percentage of all breast cancer cases attributable to this risk factor, 2.5%). A similar gene-environment association was observed for the exon 7 polymorphism (RR, 3.61; 95% CI, 1.11-11.7; percentage of all breast cancer cases attributable to this risk factor, 2.2%). These data are compatible with the hypothesis that cigarette smoking early in life is a modifiable cause of breast cancer in a subpopulation of genetically susceptible women. However, the proportion of breast cancer attributable to cigarette smoking at a young age among Caucasian women with the variant form of the CYP1A1 polymorphisms is low.
环境暴露于致癌物可能导致美国乳腺癌发病率上升以及乳腺癌发病率的地理差异。一类备受关注的化学物质是多环芳烃，它们在环境中普遍存在且存在于香烟烟雾中。细胞色素P450 1A1（CYP1A1）基因编码一种有助于芳烃羟化酶活性的酶，该酶参与多环芳烃的代谢。CYP1A1的基因变体与芳烃羟化酶活性增加有关，一些流行病学研究表明，具有变体基因型的女性患乳腺癌的风险增加。在护士健康研究中的一项病例对照研究中，我们前瞻性地评估了CYP1A1多态性与乳腺癌风险之间的关联，以及吸烟对这些关联的潜在影响。我们通过PCR-RFLP分析，在466例新发乳腺癌病例和466例匹配对照中分析了CYP1A1基因第6235位核苷酸（MspI）的T→C转换和第4889位核苷酸（外显子7）的A→G转换。使用条件逻辑回归，相对风险（RRs）和95%置信区间（CIs）用于量化至少有一个变体等位基因的受试者相对于野生型等位基因纯合子受试者患乳腺癌的风险。CYP1A1变体基因型并未使乳腺癌风险总体增加（RR(MspI)，1.05；95%CI，0.74 - 1.50；RR(外显子7)，0.88；95%CI，0.58 - 1.33）。然而，与该多态性野生型纯合子的非吸烟者相比，18岁前开始吸烟且具有CYP1A1-MspI变体基因型的女性患乳腺癌风险有提示性增加（RR，5.65；95%CI，1.50 - 21.3；该风险因素导致的所有乳腺癌病例的百分比，2.5%）。外显子7多态性也观察到类似的基因-环境关联（RR，3.61；95%CI，1.11 - 11.7；该风险因素导致的所有乳腺癌病例的百分比，2.2%）。这些数据与以下假设相符：早年吸烟是遗传易感女性亚群中乳腺癌的一个可改变的病因。然而，在具有CYP1A1多态性变体形式的白人女性中，年轻时吸烟导致的乳腺癌比例较低。
