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

描述（由申请人提供）： 卵巢癌是一种潜伏性疾病，也是一种强有力的杀手。预防是 这是目前降低发病率和死亡率的最佳方法。确定 病因因素和确定妇女在增加的风险是第一步 制定有效的预防方案。携带BRCA 1/2的女性 突变，预防就更加重要了，因为它们是 比一般女性更容易患上这种疾病。但 BRCA 1/2相关性乳腺癌的发病率和发病年龄存在相当大的差异， 疾病表明存在共同的、改变因素。识别此类 因素很重要，因为它将使我们能够制定风险战略， 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，改变卵巢癌可用性的因素 这些激素可能会影响卵巢癌的风险， 载波性类固醇途径基因沿着的多态性可能是这样的 因素越来越多的证据表明，这些多态性在几个 与乳腺癌有关的疾病，如乳腺癌。还有证据表明 这些基因变异在卵巢癌中的作用。BRCA 1的新作用 在DNA修复中的研究表明DNA修复基因多态性与 BRCA 1/2相关疾病没有研究探讨过这些可能性。我们将 进行病例对照研究，以确定这些多态性的影响 卵巢癌的风险在一般和BRCA 1/2携带者。我们还将 确定外源性和内源性激素因素改变与这些多态性相关的风险的程度。我们将获得基因型数据 使用了300名德系犹太妇女的DNA库， 侵袭性上皮性卵巢癌和300名健康德系犹太妇女 按5岁年龄组与病例相匹配的频率。女性此前 参加了一项由国家癌症研究所资助的卵巢癌流行病学研究， 犹太女人详细的妇科和生殖史数据， 母研究已经使用标准化的面对面测试获得了 采访还获得了DNA并用于确定BRCA 1/2状态。 研究参与者。这项研究将确定最有希望的等位基因 我们将进一步研究这些基因之间的变异， 一项大型、多国人群病例对照研究。本研究将 还发展进行多国研究所需的基础设施 研究卵巢癌的遗传和环境决定因素。的 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.