Goodman M T, McDuffie K, Kolonel L N, Terada K, Donlon T A, Wilkens L R, Guo C, Le Marchand L
Cancer Etiology Program, Cancer Research Center, University of Hawaii, Honolulu 96813, USA.
Cancer Epidemiol Biomarkers Prev. 2001 Mar;10(3):209-16.
Steroid hormones, such as estrogens, appear to be associated with ovarian carcinogenesis, but the precise biological mechanisms are unclear. Polymorphisms in genes that regulate the concentration of estrogens and their metabolites may contribute directly to the individual variation in ovarian cancer risk through a mechanism involving oxidative stress or indirectly by influencing ovarian cancer susceptibility associated with ovulation and reproduction. We conducted a population-based, case-control study of primary ovarian cancer between 1993 and 1999 in Hawaii to test several genetic and related hypotheses. A personal interview and blood specimen were obtained in the subjects' homes. In a sample of 129 epithelial ovarian cancer cases and 144 controls, we compared the frequencies of several polymorphisms in genes that regulate steroid hormone metabolism and catecholestrogen formation. Multivariate unconditional logistic regression was used to model the association of each genetic polymorphism separately after adjusting for age, ethnicity, and other covariates. The high-activity Val432 allele of the CYP1B1 gene, which may be linked to oxidative stress through elevated 4-hydroxylated catecholestrogen formation, was associated with an increased risk of ovarian cancer. The Val/Leu genotype for CYP1B1 was associated with an odds ratio of 1.8 (95% confidence interval, 1.0-3.3) and the Val/Val genotype with an odds ratio of 3.8 (95% confidence interval, 1.2-11.4) compared with the Leu/Leu genotype (P = 0.005). Tobacco smokers with at least one CYP1A1 (MspI) m2 allele, one CYP1B1 Val allele, one COMT Met allele, or two CYP1A2 A alleles were at significantly increased risk of ovarian cancer compared to never-smokers with CYP1A1 (MspI) ml/ml, CYP1B1 Leu/Leu, COMT Val/Val, or CYP1A2 A/A genotypes, respectively. We found a positive statistical interaction (P = 0.03) between tobacco smoking and the CYP1A1 (MspI) polymorphism on the risk of ovarian cancer. None of the other gene-environment (pregnancy, oral contraceptive pill use) or gene-gene interactions were statistically significant. Although not significant, there was a suggestion that the effect of the CYP1B1 Val allele was reduced substantially in the presence of the high-activity COMT Met allele. These findings suggest that the CYP1B1-Val allele and perhaps other genetic polymorphisms in combination with environmental or hormonal exposures are susceptibility factors for ovarian cancer.
类固醇激素，如雌激素，似乎与卵巢癌发生有关，但确切的生物学机制尚不清楚。调节雌激素及其代谢产物浓度的基因多态性可能通过涉及氧化应激的机制直接导致卵巢癌风险的个体差异，或通过影响与排卵和生殖相关的卵巢癌易感性间接导致这种差异。1993年至1999年期间，我们在夏威夷进行了一项基于人群的原发性卵巢癌病例对照研究，以检验几个遗传学及相关假说。在受试者家中进行了个人访谈并采集了血样。在129例上皮性卵巢癌病例和144例对照的样本中，我们比较了调节类固醇激素代谢和儿茶酚雌激素形成的基因中几种多态性的频率。在调整年龄、种族和其他协变量后，使用多变量无条件逻辑回归分别对每种基因多态性的关联进行建模。CYP1B1基因的高活性Val432等位基因可能通过增加4-羟基化儿茶酚雌激素的形成与氧化应激相关联，与卵巢癌风险增加有关。与Leu/Leu基因型相比，CYP1B1的Val/Leu基因型的优势比为1.8（95%置信区间，1.0 - 3.3），Val/Val基因型的优势比为3.8（95%置信区间，1.2 - 11.4）（P = 0.005）。与分别具有CYP1A1（MspI）ml/ml、CYP1B1 Leu/Leu、COMT Val/Val或CYP1A2 A/A基因型的从不吸烟者相比，至少携带一个CYP1A1（MspI）m2等位基因、一个CYP1B1 Val等位基因、一个COMT Met等位基因或两个CYP1A2 A等位基因的吸烟者患卵巢癌的风险显著增加。我们发现吸烟与CYP1A1（MspI）多态性之间在卵巢癌风险上存在统计学上的正交互作用（P = 0.03）。其他基因 - 环境（怀孕、口服避孕药使用）或基因 - 基因相互作用均无统计学意义。尽管不显著，但有迹象表明在存在高活性COMT Met等位基因的情况下，CYP1B1 Val等位基因的作用大幅降低。这些发现表明，CYP1B1 - Val等位基因以及可能的其他基因多态性与环境或激素暴露相结合是卵巢癌的易感因素。
