GENES AND THE ESTROGEN EFFECT ON ENDOMETRIAL CANCER

描述（由申请人提供）：子宫内膜癌的病因是 相对比较好理解。雌激素对子宫内膜的刺激， 孕激素的调节作用是主要原因。雌激素替代 绝经期雌激素替代治疗（ERT）和肥胖是主要的危险因素。的 后者的影响可能是由于绝经后 肥胖和循环中生物可利用的雌激素水平。口服避孕药和 怀孕，这两种方式都能刺激子宫内膜， 与孕激素的持续调节作用有关， 降低风险。联合激素替代疗法，其中， 在整个或部分月经周期中加入雌激素， 子宫内膜癌风险高于非激素使用者 更换.尽管ERT和肥胖是主要的风险因素， 只有一小部分使用ERT的女性甚至是极度肥胖的女性 患上子宫内膜癌从公共卫生角度来看， 从机械论的角度来预测哪些女性会被淘汰。我们 建议评估一系列的八个候选基因（CYP 17，CYP 19，HSD17 B1， ER、CYP1A1、CYP1B1、COMT和PR）在雌激素生物合成、反式激活 和代谢途径，以确定这些风险因素的影响是否可能 由遗传变异性介导或修饰。我们将评估这个问题 在一项对133，000名女性进行的前瞻性流行病学研究中， 加州教师（加州教师研究）使用嵌套病例对照 设计我们还将详细研究植物雌激素对 子宫内膜癌风险降低与HRT，肥胖和 八个候选基因正在评估中。

DESCRIPTION (provided by applicant): The etiology of endometrial cancer is relatively well understood. Estrogen stimulation of the endometrium without the modulatory effects of progestins is the major cause. Estrogen replacement therapy (ERT) in menopause and obesity are the principal risk factors. The effect of the latter is probably due to the association between postmenopausal obesity and circulating bioavailable estrogen levels. Oral contraceptives and pregnancy, both of which deliver estrogen stimulation to the endometrium but with the continuous modulatory influence of progestins, are associated with reduction in risk. Combination hormone replacement therapy in which a progestin is added to estrogen for all or part of the monthly cycle results in no increase in endometrial cancer risk over that of a non-user of hormone replacement. Despite the fact that ERT and obesity are the major risk factors, only a small proportion of women using ERT or even with extreme obesity will develop endometrial cancer. It would be important from a public health as well as from a mechanistic view to be able to predict which women those will be. We propose to evaluate a series of eight candidate genes (CYP17, CYP19, HSD17B1, ER, CYP1A1, CYP1B1, COMT andPR) in the estrogen biosynthesis, transactivation and metabolism pathways to determine if the effects of these risk factors might be mediated or modified by genetic variability. We will evaluate this question in the context of a prospective epidemiologic study of 133,000 female California teachers (the California Teachers Study) using a nested case-control design. We will also examine in detail the possible impact of phytoestrogens on endometrial cancer risk reduction in conjunction with HRT, obesity and the eight candidate genes under evaluation.