Hormones, DNA Repair, BRCA1/2 and Ovarian Cancer Preven*

描述(由申请人提供)： 卵巢癌是一种潜伏的疾病，也是一种强有力的杀手。预防是 目前降低发病率和死亡率的最好方法。确定 第一步是找出病因，找出高危女性 在制定有效的预防计划方面。适用于携带BRCA1/2的女性 突变，预防甚至更加关键，因为它们是 比一般女性更容易患上这种疾病。然而， BRCA1/2相关的外显率和年龄在发病时有相当大的变异性 疾病表明存在共同的、修饰性的因素。确定这样的 因素很重要，因为它将使我们能够制定应对风险的战略 评估和有针对性的预防工作。性类固醇激素一直是 与卵巢癌有关；因此，改变可获得的因素 这些激素可以影响卵巢癌的总体风险和BRCA1/2 承运人。性类固醇途径基因的多态可能就是这样的 各种因素。越来越多的证据表明，这些多态在几个 与激素相关的疾病，如乳腺癌。也有证据表明 这些基因变异在卵巢癌中的作用。BRCA1的新角色 在DNA修复中提示DNA修复基因的多态和 BRCA1/2相关疾病。目前还没有研究对这些可能性进行检验。我们会 进行一项病例对照研究以确定这些多态的影响 总体上和BRCA1/2携带者之间的卵巢癌风险。我们还将 确定外源性和内源性激素因素改变与这些多态相关的风险的程度。我们将获得基因数据 使用来自300名经组织学证实的德系犹太妇女的银行DNA 侵袭性上皮性卵巢癌与300名健康的德系犹太妇女 5岁年龄组与病例匹配的频率。之前的女性 年参与了NCI资助的卵巢癌流行病学研究 犹太女人。关于妇科和生育史的详细数据 已由家长研究使用标准化的面对面调查获得 面试。还获得了DNA，并用于确定BRCA1/2状态 研究参与者。这项研究将确定最有希望的等位基因 建议基因中的变异，我们将在 大型多民族人群病例对照研究。这项研究将 还开发进行多国研究所需的基础设施 检查卵巢癌的遗传和环境决定因素。这个 我们将收集的专业知识和数据将促进未来的创新研究 了解卵巢癌。

DESCRIPTION (provided by applicant): Ovarian cancer is an insidious disease and a potent killer. Prevention is currently the best way to reduce morbidity and mortality. Determining etiologic factors and identifying women at an increased risk is the first step in devising an effective prevention program. For women carrying a BRCA1/2 mutation, prevention is even more critical because they are 10 times more likely to develop the disease than women are in general. However, the considerable variability in penetrance and age at onset of BRCA1/2-associated disease suggests the existence of common, modifying factors. Identifying such factors is important because it will enable us to develop strategies for risk assessment and targeted prevention efforts. Sex steroid hormones have been implicated in ovarian cancer; thus, factors that alter the availability of these hormones could impact ovarian cancer risk in general and among BRCA1/2 carriers. Polymorphisms in genes along the sex steroid pathways may be such factors. Evidence is mounting for a role of these polymorphisms in several hormonally-related diseases, such as breast cancer. There is also evidence of a role for these gene variants in ovarian cancer. The emerging role of BRCA1 in DNA repair suggests a link between DNA repair genes polymorphisms and BRCA1/2-associated disease. No study has examined these possibilities. We will undertake a case-control study to determine the effects of these polymorphisms on ovarian cancer risk in general and among BRCA1/2 carriers. We will also determine the degree to which exogenous and endogenous hormonal factors modify the risk associated with these polymorphisms. We will obtain genotype data using banked DNA from 300 Ashkenazi Jewish women with histologically-confirmed invasive epithelial ovarian cancer and 300 healthy Ashkenazi Jewish women frequency matched by 5-year age groups to cases. The women previously participated in an NCI-funded study of the epidemiology of ovarian cancer in Jewish women. Detailed data on gynecologic and reproductive history have already been obtained by the parent study using a standardized in-person interview. DNA was also obtained and used to determine the BRCA1/2 status of study participants. This study will identify the most promising allelic variants among the proposed genes, which we will further investigate in a large, multi-national population-based case-control study. This study will also develop the infrastructure needed to undertake a multi-national study examining genetic and environmental determinants of ovarian cancer. The expertise and data we will collect will promote future innovative research into understanding ovarian cancer.