Genome-wide Copy Number Variation and Breast Cancer Risk

描述（由申请人提供）：这是一项加速重新提交的资助申请，一项乳腺癌全基因组拷贝数变异研究（R 01 CA 137013）。乳腺癌是美国和世界许多其他地区妇女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，通常被用作遗传标记进行遗传关联研究。已经研究了100多个与乳腺癌风险有关的候选基因，然而，只有少数基因被复制。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风险因素。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。最近，大的DNA片段重复和/或缺失，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SNPs占更多的核苷酸变异，它们可能是乳腺癌遗传易感性的一个未被认识的来源。越来越多的报道，如家族性乳腺癌，胰腺癌，前列腺癌，自闭症等，CNVs和人类疾病之间的强关联。我们建议调查与乳腺癌相关的CNVs的整个人类基因组。本申请中提出的多阶段CNV GWA将建立在由NCI资助的三项大型、正在进行的研究中建立的资源基础上，NCI是最近支持的乳腺癌全基因组关联研究（R 01 CA 124558），上海乳腺癌研究（R 01 CA 64277）-一项基于人群的病例对照研究，以及上海女性健康研究（RO 1 CA 70867）-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例对照中进行全基因组CNV扫描。我们最近通过使用Affytron 6.0阵列完成了1，353例病例和1，349例对照的第I阶段基因分型，作为现有SNP GWA研究（RO 1 CA 124558）的一部分。来自这2,702个样本的阵列中包含的约100万个SNP和100万个非多态性探针的强度数据将可用于这项拟议的研究，以调用CNV。这些CNV与乳腺癌风险的关联将被研究。在第二阶段，将选择500个最有希望的CNV，在1,500例病例和1,500例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将在从前瞻性SWHS中选择的1,000个病例和2,000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，具有许多独特的功能，有助于严格评估乳腺癌遗传因素。这项研究的结果将有助于确定高危妇女进行乳腺癌的一级和二级预防。由于I期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，因此该项目将非常有效。 公共卫生相关性：乳腺癌是美国和世界许多其他地区妇女中最常见的恶性肿瘤。最近，大的DNA片段重复和/或缺失，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，“全基因组拷贝数变异和乳腺癌风险（R 01 CA 137013）”，通过利用三项大规模研究的资源，调查整个人类基因组中与乳腺癌相关的CNV。

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.