Genome-wide Copy Number Variation and Breast Cancer Risk

描述(由申请人提供)：这是一份快速重新提交的拨款申请，一项乳腺癌全基因组拷贝数变异研究(R01CA137013)。乳腺癌是美国和世界其他许多地区女性最常见的恶性肿瘤。遗传因素在乳腺癌的病因中起着重要作用。单核苷酸多态(SNPs)被认为是基因组变异的主要形式，在遗传关联研究中被广泛用作遗传标记。超过100个候选基因与乳腺癌风险相关，然而，其中只有几个基因被复制。最近，全基因组关联(GWA)研究发现了这种常见恶性肿瘤的新的遗传危险因素。然而，SNP标记不太可能完全解释乳腺癌的遗传变异，因为存在其他重要的遗传变异。近年来，被称为拷贝数变异(CNV)的DNA大片段复制和/或缺失在人类基因组中频繁发生。与SNPs相比，CNV引起更多的核苷酸变异，它们可能是乳腺癌遗传易感性的一个未被认识的来源。CNV与人类疾病的相关性越来越强，如家族性乳腺癌、胰腺癌、前列腺癌、自闭症等。我们建议调查整个人类基因组中与乳腺癌相关的CNV。本申请中建议的多阶段CNV GWA将建立在NCI资助的三项正在进行的大型研究中的资源基础上，这三项研究是最近支持的乳腺癌全基因组相关性研究(R01 CA124558)、上海乳腺癌研究(R01 CA64277)-基于人群的病例对照研究，以及上海妇女健康研究(RO1 CA70867)-基于人群的前瞻性队列研究。在第一阶段，我们将对1,353例患者和1,349名对照进行全基因组CNV扫描。作为现有SNP GWA研究(RO1 CA124558)的一部分，我们最近使用Affymetrix 6.0阵列完成了1,353例患者和1,349名对照的I阶段基因分型。来自这2,702个样本的阵列中约100万个SNP和100万个非多态探针的强度数据将可用于这项拟议的研究，称为CNV。这些CNV与乳腺癌风险的关系将被调查。在第二阶段，500个最有希望的CNV将被选为在1500个病例和1500个对照的独立样本中进行验证。在第三阶段，最有希望的30个CNV将在1000个病例和2000个对照中进一步验证，这些病例和对照是从未来的SWHS中挑选出来的。这项新提出的研究的母项目进行得非常好，具有很强的方法学。这项研究是独一无二的，具有许多独特的特征，有助于对乳腺癌遗传因素进行严格评估。这项研究的结果将对确定乳腺癌一级和二级预防的高危妇女有价值。由于第一阶段的数据和标本收集得到了现有研究的支持，并使用了多阶段研究设计，因此该项目将非常有效。公共卫生相关性：乳腺癌是美国和世界其他许多地区女性最常见的恶性肿瘤。近年来，被称为拷贝数变异(CNV)的DNA大片段复制和/或缺失在人类基因组中频繁发生。我们提出了这项名为《基因组广泛拷贝数变异与乳腺癌风险(R01CA137013)》的研究，旨在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。

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.