Genome-wide Copy Number Variation and Breast Cancer Risk

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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.