COHORT STUDY OF GENETIC SUSCEPTIBILITY TO BREAST CANCER

我们建议使用两个具有良好特征的大型队列的资源 评估基因风险的研究(护士健康研究I和II) 乳腺癌的致病因素。我们将量化罕见的HRAS1的关联 和乳腺癌的等位基因，并测试这种关联是否被修改 已知的乳腺癌危险因素。我们将评估 在队列中的病例中检测BRCA1的突变，并测试是否 生殖和其他乳腺癌危险因素的分布情况如下 BRCA1胚系突变病例与无BRCA1胚系突变病例之间存在差异。这些 分析将嵌套在来自护士医院的33,000名女性的子队列中 在1989-90年间提供血液样本的健康研究I，因此将是 能够前瞻性地检查这些问题的为数不多的研究 完全查明事件案例的队列和全面的 关于其他乳腺癌风险因素的前瞻性信息。此外, 我们将从护士健康中心的病例和对照中获取血液样本 研究二，一组年轻女性。在这两项研究中，我们预计 基因分型1280例。将两个对照与每个病例匹配，我们将获得98% 检测相对风险的能力为2.0，检测相对风险的能力为80% 1.5的风险与罕见的HRAS1等位基因有关。我们会有 研究HRAS1等位基因与其他基因相互作用的强大力量 乳腺癌的危险因素。尽管BRCA1检测和检测的成本 突变的罕见排除了检测BRCA1突变的对照， 通过确定已定义病例系列中的BRCA1突变的谱， 我们将提供有关个人发病机制的信息。 突变。我们将有足够的能力对案件进行分析，以发现 BRCA1突变与其他乳腺癌风险的中度交互作用 各种因素。这些研究的结果将为以下方面提供可靠的信息 这些风险的遗传标记，以及定义生殖和 与他们相互作用的生活方式因素。这款产品的可用性 信息对我们为女性提供适当咨询的能力至关重要 这些基因类型。

We propose to use the resources of two large well-characterized cohort studies (the Nurses' Health Study I and II) to assess genotypic risk factors for breast cancer. We will quantify the association of rare HRAS1 alleles with breast cancer and test whether this association is modified by known breast cancer risk factors. We will assess the frequency of mutations in BRCA1 among cases from the cohort, and test whether the distribution of reproductive and other breast cancer risk factors is different between cases with and without BRCA1 germline mutations. These analyses will be nested in the subcohort of 33,000 women from Nurses' Health Study I who gave blood samples in 1989-90, and thus, will be among the few studies able to prospectively examine these issues in a defined cohort with complete ascertainment of incident cases and comprehensive prospective information on other breast cancer risk factors. In addition, we will obtain blood specimens from cases and controls in Nurses' Health Study II, a cohort of younger women. Across both studies we expect to genotype 1,280 cases. Matching two controls to each case we will have 98% power to detect a relative risk of 2.0, and 80% power to detect a relative risk of 1.5 associated with the rare HRAS1 alleles genotype. We will have substantial power to examine interactions of HRAS1 alleles with other breast cancer risk factors. Although the cost of the BRCA1 assays and rarity of the mutations precludes assaying controls for BRCA1 mutations, by determining the spectrum of BRCA1 mutations in a defined case series, we will contribute information on the pathogenesis of individual mutations. We will have adequate power in case-case analyses to detect moderate interactions between BRCA1 mutations and other breast cancer risk factors. The results from these studies will provide firm information on these genetic markers of risk, as well as defining reproductive and lifestyle factors which interact with them. The availability of this information is critical to our ability to appropriately counsel women with these genotypes.