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

辐射暴露与双侧乳腺癌的全基因组关联研究

• 批准号: 8051549
• 负责人: JONINE L. BERNSTEIN
• 金额: $ 305.74万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8051549
• 关键词: Accounting; Applications Grants; BRCA1 gene; BRCA2 gene; Bilateral; Biochemical Pathway; Blood specimen; Breast; Breast Cancer Risk Factor; CHEK2 gene; Cancer Control; Candidate Disease Gene; Case-Control Studies; Complex; Contralateral; Coupled; DNA Damage; Data; Denmark; Diagnosis; Disease; Dose; Environmental Exposure; Environmental Risk Factor; Etiology; Exposure to; Funding; Future; Genes; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genomics; Genotype; Goals; Health; Incidence; Individual; Interview; Ionizing radiation; Joints; Malignant Neoplasms; Maps; Modeling; Mutate; Nested Case-Control Study; Parents; Participant; Population; Population Study; Predisposition; Prevention; Public Health; Publishing; Radiation; Radiation Scattering; Radiation induced double strand break; Radiation therapy; Recruitment Activity; Research Design; Risk; Risk Factors; Role; Sampling; Screening procedure; Single Nucleotide Polymorphism; Staging; Susceptibility Gene; Testing; Validation; Variant; Woman; base; bilateral breast cancer; cancer diagnosis; case control; design; gene environment interaction; genetic epidemiology; genetic risk factor; genetic variant; genome wide association study; improved; insight; malignant breast neoplasm; neoplasm registry; novel; population based; response; therapeutic target

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.

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，我们建议对患有双侧乳腺癌的女性应用全基因组关联（GWA）方法，我们对其有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 1,399 名患有单侧乳腺癌的女性（匹配对照）。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、访谈并获取 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：在基于人群的病例对照研究中采用两阶段方法识别与双侧乳腺癌相关的 SNP。在发现的第一阶段，对双侧和单侧乳腺癌进行 GWA 研究，以使用现有病例和对照来识别与双侧乳腺癌发病率相关的常见 SNP。在验证的第 2 阶段，评估第 1 阶段在新病例和新对照中确定的 6,000 个最重要的 SNP。目标 2：识别与辐射暴露相互作用的 SNP。使用与目标 1 相同的两阶段设计，纳入有关辐射暴露的详细信息，以发现和验证与辐射暴露相互作用的 6,000 个最重要的常见 SNP，并降低发生第二原发性乳腺癌的风险。目标 3：利用整个 WECARE 研究群体，确定通过独立 GWA 研究确定的与单侧乳腺癌相关的基因组区域是否也与患双侧乳腺癌或辐射诱发乳腺癌的风险相关。目标 4：在基于人群的病例对照研究设计中表征包含与双侧乳腺癌和/或辐射诱发乳腺癌相关变异的基因组区域。与目标 1、2 或 3 中确定的潜在因果 SNP 相关的 10 个最强烈相关的区域将通过重新测序来进一步表征，以识别其他变异，从而对这些区域进行更精细的绘图。我们将对 3,707 名女性的整个研究人群中的假定疾病相关和/或功能性遗传变异进行基因分型。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，以及一般放射源性癌症的易感性。公共卫生相关性：乳腺癌是一种异质性疾病，具有多种遗传和环境原因。这项全基因组关联研究的重点是患有双侧乳腺癌的女性（“病例”）和患有单侧乳腺癌的女性（“对照”），这些女性可能因遗传原因而增强，目的是确定影响乳腺癌和可能的放射性癌症易感性的新遗传因素。这项研究的结果将对乳腺癌女性的长期管理以及有针对性的治疗和预防工作产生重要影响。