Genome-wide Copy Number Variation and Breast Cancer Risk

描述（由申请人提供）：这是一项资助申请的加速再提交，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上许多其他地区女性中最常见的恶性肿瘤。遗传因素在乳腺癌的病因学中起重要作用。单核苷酸多态性（SNPs）被认为是基因组变异的主要形式，在遗传关联研究中常被用作遗传标记。超过100种与乳腺癌风险相关的候选基因已被研究，然而，其中只有少数被复制。最近，全基因组关联（GWA）研究已经确定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，大量DNA片段重复和/或缺失，被称为拷贝数变异（CNV），已被证明经常发生在人类基因组中。CNVs比snp的核苷酸变异更多，它们可能是乳腺癌遗传易感性的一个未被认识的来源。CNVs与家族性乳腺癌、胰腺癌、前列腺癌、自闭症等人类疾病之间的密切关联越来越多地被报道。我们建议调查整个人类基因组中与乳腺癌相关的CNVs。本申请中提出的多期CNV GWA将建立在由NCI资助的三个正在进行的大型研究的基础上：最近支持的乳腺癌全基因组关联研究（R01 CA124558），上海乳腺癌研究(R01 CA64277) -一项基于人群的病例对照研究，以及上海妇女健康研究(RO1 CA70867) -一项基于人群的前瞻性队列研究。在第一阶段，我们将对1353例病例和1349例对照进行全基因组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1353例病例和1349例对照的I期基因分型。来自这2702个样本的约100万个snp和100万个非多态性探针的强度数据将可用于该研究，以称为CNVs。这些CNVs与乳腺癌风险的关系将被调查。在第二阶段，将选择500个最有希望的CNVs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CNVs将在1000个病例和2000个对照中进一步验证。这项新提出的研究的母项目以强有力的方法进行得非常好。这项研究是独一无二的，有许多独特的特点，有助于对乳腺癌遗传因素进行严格的评估。这项研究的结果将对确定高危妇女进行乳腺癌的一级和二级预防有价值。由于第一阶段的数据和标本收集得到现有研究的支持，并采用多阶段研究设计，因此该项目将非常高效。公共卫生相关性：乳腺癌是美国和世界上许多其他地区妇女中最常见的恶性肿瘤。近年来，大量DNA片段重复和/或缺失，被称为拷贝数变异（CNV），已被证明经常发生在人类基因组中。我们提出这项研究，“基因组宽拷贝数变异和乳腺癌风险（R01CA137013）”，通过利用三个大规模研究的资源来调查与乳腺癌相关的整个人类基因组的CNVs。

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.