Genome-wide Copy Number Variation and Breast Cancer Risk

全基因组拷贝数变异和乳腺癌风险

• 批准号: 8078089
• 负责人: Jirong Long
• 金额: $ 59.67万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8078089
• 关键词: Accounting; Address; Admixture; Adult; Applications Grants; Asians; Autistic Disorder; Biological; Breast Cancer Genetics; Breast Cancer Risk Factor; Cancer-Predisposing Gene; Candidate Disease Gene; Case-Control Studies; Clinical Data; Cohort Studies; Communities; Copy Number Polymorphism; DNA; Data; Data Collection; Environmental Risk Factor; Epidemiologic Studies; Etiology; Evaluation; Exposure to; Funding; General Population; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic Variation; Genome; Genomics; Genotype; Health; Hereditary Breast Carcinoma; High Risk Woman; Human; Human Genome; Interview; Investigation; Malignant Neoplasms; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Methodology; Nested Case-Control Study; Nucleotides; Oncogenes; Persons; Phase; Play; Population; Predisposition; Primary Prevention; Recruitment Activity; Reporting; Research Design; Resources; Risk Factors; Role; Sampling; Scanning; Secondary Prevention; Signal Transduction; Single Nucleotide Polymorphism; Source; Staging; Surveys; Time; United States; Validation; Variant; Woman; Women' s Health; cancer risk; comparative genomic hybridization; cost; gene discovery; genetic association; genetic risk factor; genome wide association study; genome-wide; human disease; malignant breast neoplasm; non-genetic; novel; parent project; population based; prospective; response; sample collection

DESCRIPTION (provided by applicant): This is an expedited resubmission of a grant application, a genome-wide copy number variation study of breast cancer (R01CA137013). Breast cancer is the most common malignancy among women in the United States and many other parts of the world. Genetic factors play an important role in the etiology of breast cancer. Single nucleotide polymorphisms (SNPs) were thought to be the predominant form of genomic variation and were commonly used as genetic markers in genetic association studies. Over 100 candidate genes have been investigated in relation to breast cancer risk, however, only a few of them, have been replicated. Recently, genome wide association (GWA) studies have identified novel genetic risk factors for this common malignancy. However, it is unlikely that SNP markers could entirely explain genetic variation for breast cancer as other important genetic variations exist. Recently, large DNA fragment duplication and/or deletion, termed as copy number variation (CNV), has been shown to frequently occur in the human genome. CNVs account for more nucleotide variation than SNPs and they may be an unrecognized source of breast cancer genetic susceptibility. Strong associations between CNVs and human diseases are increasingly reported such as familial breast cancer, pancreatic cancer, prostate cancer, autism, etc. We propose to survey the entire human genome for CNVs associated with breast cancer. The multi-phase CNV GWA proposed in this application will be built upon the resources established in three large, on-going studies funded by NCI, a recently supported `Genome-wide association study for breast cancer (R01 CA124558), the Shanghai Breast Cancer Study (R01 CA64277) - a population-based case-control study, and the Shanghai Women's Health Study (RO1 CA70867) - a population-based prospective cohort study. In Phase I, we will conduct a genome wide CNV scan in 1,353 cases and 1,349 controls. We have recently completed Stage I genotyping for 1,353 cases and 1,349 controls by using Affymetrix 6.0 array as part of an existing SNP GWA study (RO1 CA124558). Intensity data from around one million SNPs and one million non-polymorphic probes included in the array for these 2,702 samples will be available for this proposed study to call CNVs. Associations of these CNVs with breast cancer risk will be investigated. In Phase II, the 500 most promising CNVs will be selected for validation in an independent sample of 1,500 cases and 1,500 controls. In Phase III, the most promising 30 CNVs will be further validated in 1,000 cases and 2,000 controls selected from the prospective SWHS. The parent projects of this newly-proposed study have been exceptionally well-conducted with a strong methodology. The study is unique and has many unique features that facilitate a rigorous evaluation of breast cancer genetic factors. The results from the study will be valuable in identifying high risk women for primary and secondary prevention of breast cancer. Because Phase I data and specimen collection are supported by the existing studies and the use of a multi-phase study design, this project will be very efficient. PUBLIC HEALTH RELEVANCE: Breast cancer is the most common malignancy among women in the United States and many other parts of the world. Recently, large DNA fragment duplication and/or deletion, termed as copy number variation (CNV), has been shown to frequently occur in the human genome. We propose this study, 'Genome wide copy number variation and breast cancer risk (R01CA137013),' to survey the entire human genome for CNVs associated with breast cancer by capitalizing the resources from three large scale studies.

描述（由申请人提供）：这是授予申请的快速重新提交，这是乳腺癌的全基因组拷贝数变异研究（R01CA137013）。乳腺癌是美国妇女和世界许多其他地区中最常见的恶性肿瘤。遗传因素在乳腺癌的病因中起重要作用。单核苷酸多态性（SNP）被认为是基因组变异的主要形式，在遗传关联研究中通常被用作遗传标记。已经研究了超过100个候选基因，这些基因与乳腺癌的风险有关，但是，仅重复了其中的少数候选基因。最近，基因组广泛的关联（GWA）研究确定了这种常见恶性肿瘤的新遗传危险因素。但是，由于存在其他重要的遗传变异，SNP标记不太可能完全解释乳腺癌的遗传变异。最近，已显示在人基因组中经常出现大型DNA片段重复和/或缺失，称为拷贝数变化（CNV）。 CNV占核苷酸变化的量比SNP的变化更多，并且它们可能是乳腺癌遗传易感性的未识别来源。越来越多地报道了CNV与人类疾病之间的密切相关性，例如家族性乳腺癌，胰腺癌，前列腺癌，自闭症等。我们建议我们调查与乳腺癌相关的CNV的整个人类基因组。 The multi-phase CNV GWA proposed in this application will be built upon the resources established in three large, on-going studies funded by NCI, a recently supported `Genome-wide association study for breast cancer (R01 CA124558), the Shanghai Breast Cancer Study (R01 CA64277) - a population-based case-control study, and the Shanghai Women's Health Study (RO1 CA70867) -一项基于人群的前瞻性队列研究。在第一阶段，我们将在1,353例病例和1,349个对照中进行基因组宽的CNV扫描。我们最近通过使用Affymetrix 6.0阵列作为现有SNP GWA研究的一部分（RO1 CA124558），对1,353例病例和1,349个对照完成了I期基因分型。该拟议的研究将提供来自这2702个样本的阵列中的大约一百万个SNP和100万个非晶型探针的强度数据，以致电CNV。这些CNV与乳腺癌风险的关联将被研究。在第二阶段，将在1,500例和1,500个对照的独立样本中选择500个最有希望的CNV进行验证。在第三阶段中，最有希望的30个CNV将在1,000例病例中进一步验证，并从预期的SWH中选择了2,000例对照。这项新提出的研究的父项目与强有力的方法相当良好。该研究是独特的，并且具有许多独特的特征，可促进对乳腺癌遗传因素进行严格评估。这项研究的结果对于确定乳腺癌的原发性和继发性预防高风险女性将很有价值。由于I期数据和标本的收集得到了现有研究的支持，并且使用了多相研究设计，因此该项目将非常有效。 公共卫生相关性：乳腺癌是美国妇女和世界许多其他地区中最常见的恶性肿瘤。最近，已显示在人基因组中经常出现大型DNA片段重复和/或缺失，称为拷贝数变化（CNV）。我们提出了这项研究，“基因组宽拷贝数变异和乳腺癌风险（R01CA137013）”，通过利用三项大规模研究的资源来调查与乳腺癌相关的CNV的整个人类基因组。