Genome-Wide Association Study of Radiation Exposure and Bilateral Breast Cancer

描述（由申请人提供）：为了描述遗传易感性和辐射暴露在第二原发性乳腺癌病因学中的共同作用，我们建议对双侧乳腺癌女性患者应用全基因组关联（GWA）方法，我们已经对其进行了详细的辐射剂量估计。现有的研究人群包括708名患有非同步双侧乳腺癌的女性（病例）和1399名患有单侧乳腺癌的女性（配对对照）。此外，通过美国的四个癌症登记处和丹麦的一个癌症登记处，我们将招募，采访并获取800名双侧乳腺癌女性（新病例）和800名单侧乳腺癌女性（新对照）的血液样本。我们的具体目标如下：目标1：在一项基于人群的病例对照研究中，采用两阶段方法确定与双侧乳腺癌相关的snp。在发现的第一阶段，使用现有病例和对照，对双侧和单侧乳腺癌进行GWA研究，以确定与双侧乳腺癌发病率相关的常见snp。在验证的第二阶段，评估第一阶段在新病例和新对照中发现的6000个最重要的snp。目标2：确定似乎与辐射暴露相互作用的snp。使用与Aim 1相同的两阶段设计，纳入辐射暴露的详细信息，以发现和验证与辐射暴露相互作用并改变患第二原发性乳腺癌风险的6000个最重要的常见snp。目的3：利用整个WECARE研究人群，确定通过独立GWA研究发现的与单侧乳腺癌相关的基因组区域是否也与发生双侧乳腺癌或辐射诱导乳腺癌的风险相关。目的4：在基于人群的病例对照研究设计中，描述包含与双侧乳腺癌和/或辐射诱导乳腺癌相关变异的基因组区域。在目标1、2和3中发现的10个与潜在的因果snp相关的最密切相关的区域将通过重新测序进一步表征，以确定这些区域更精细的映射的其他变体。我们将对3,707名女性的整个研究人群进行基因分型，推测疾病相关和/或功能性遗传变异。这项研究的结果将帮助我们了解影响乳腺癌易感性的遗传和环境因素，特别是对放射性癌症。公共卫生相关性：乳腺癌是一种具有多种遗传和环境原因的异质性疾病。这项全基因组关联研究的重点是双侧乳腺癌妇女（“病例”），她们可能因遗传原因而增强，以及单侧乳腺癌妇女（“对照组”），其目标是确定影响乳腺癌易感性的新遗传因素，可能是放射性致癌。这项研究的结果将对乳腺癌妇女的长期管理以及靶向治疗和预防工作具有重要意义。

DESCRIPTION (provided by applicant): To delineate the joint roles of genetic predisposition and radiation exposure in the etiology of second primary breast cancer, we propose to apply a genome-wide association (GWA) approach to women with bilateral breast cancer for whom we have detailed radiation dose estimates. The existing study population consists of 708 women with asynchronous bilateral breast cancer (cases) and 1,399 women with unilateral breast cancer (matched controls). In addition, through four cancer registries in the US and one in Denmark, we will recruit, interview and obtain a blood sample from 800 women with bilateral breast cancer (new cases) and 800 women with unilateral breast cancer (new controls). Our Specific Aims are as follows: AIM 1: Identify SNPs that are associated with bilateral breast cancer using a two-stage approach in a population-based case-control study. In Stage 1 for Discovery, perform a GWA study of bilateral and unilateral breast cancers to identify common SNPs associated with the incidence of bilateral breast cancer using the existing cases and controls. In Stage 2 for Validation, evaluate the 6,000 most significant SNPs identified in Stage 1 in the new cases and new controls. AIM 2: Identify SNPs that appear to interact with radiation exposure. Using the same two-stage design as for Aim 1, incorporate detailed information on radiation exposure to discover and validate the 6,000 most significant common SNPs that interact with radiation exposure and modify the risk of developing a second primary breast cancer. AIM 3: Using the entire WECARE Study population, determine whether genomic regions found to be associated with unilateral breast cancer as identified via independent GWA studies are also associated with risk of developing bilateral breast cancer, or radiation-induced breast cancer. AIM 4: Characterize genomic regions containing variants associated with bilateral breast cancer and/or radiation-induced breast cancer in a population-based case-control study design. The 10 most strongly implicated regions associated with potential causal SNPs identified in Aims 1, 2, or 3, will each be further characterized by re-sequencing to identify other variants for finer mapping of these regions. We will genotype putative disease associated and/or functional genetic variants in our entire study population of 3,707 women. Results from this study will help us understand genetic and environmental factors that influence susceptibility to breast cancer in particular and radiogenic cancers in general. PUBLIC HEALTH RELEVANCE: Breast cancer is a heterogenous disease with multiple genetic and environmental causes. The goal of this genome-wide association study which is focused on women with bilateral breast cancer ("cases"), who are presumably enhanced for genetic causes, and women with unilateral breast cancer ("controls") is to identify novel genetic factors that influence susceptibility to breast cancer and possibly radiogenic cancers. Results from this study will have important implications for the long-term management of women with breast cancer and for targeting therapeutic and prevention efforts.