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Grant Details

Grant Number: 5R01CA137013-04 Interpret this number
Primary Investigator: Long, Jirong
Organization: Vanderbilt University
Project Title: Genome-Wide Copy Number Variation and Breast Cancer Risk
Fiscal Year: 2012
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Abstract

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.

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Publications

Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1.
Authors: Cai Q, Zhang B, Sung H, Low SK, Kweon SS, Lu W, Shi J, Long J, Wen W, Choi JY, Noh DY, Shen CY, Matsuo K, Teo SH, Kim MK, Khoo US, Iwasaki M, Hartman M, Takahashi A, Ashikawa K, Matsuda K, Shin MH, Park MH, Zheng Y, Xiang YB, Ji BT, Park SK, Wu PE, Hsiung CN, Ito H, Kasuga Y, Kang P, Mariapun S, Ahn SH, Kang HS, Chan KY, Man EP, Iwata H, Tsugane S, Miao H, Liao J, Nakamura Y, Kubo M, DRIVE GAME-ON Consortium, Delahanty RJ, Zhang Y, Li B, Li C, Gao YT, Shu XO, Kang D, Zheng W
Source: Nat Genet, 2014 Aug;46(8), p. 886-90.
EPub date: 2014 Jul 20.
PMID: 25038754
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Rare coding variants and breast cancer risk: evaluation of susceptibility Loci identified in genome-wide association studies.
Authors: Zhang Y, Long J, Lu W, Shu XO, Cai Q, Zheng Y, Li C, Li B, Gao YT, Zheng W
Source: Cancer Epidemiol Biomarkers Prev, 2014 Apr;23(4), p. 622-8.
EPub date: 2014 Jan 27.
PMID: 24470074
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New breast cancer risk variant discovered at 10q25 in East Asian women.
Authors: Shi J, Sung H, Zhang B, Lu W, Choi JY, Xiang YB, Kim MK, Iwasaki M, Long J, Ji BT, Park SK, Zheng Y, Tsugane S, Yoo KY, Wang W, Noh DY, Han W, Kim SW, Lee MH, Lee JW, Lee JY, Shen CY, Matsuo K, Ahn SH, Gao YT, Shu XO, Cai Q, Kang D, Zheng W
Source: Cancer Epidemiol Biomarkers Prev, 2013 Jul;22(7), p. 1297-303.
EPub date: 2013 May 15.
PMID: 23677579
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Common genetic determinants of breast-cancer risk in East Asian women: a collaborative study of 23 637 breast cancer cases and 25 579 controls.
Authors: Zheng W, Zhang B, Cai Q, Sung H, Michailidou K, Shi J, Choi JY, Long J, Dennis J, Humphreys MK, Wang Q, Lu W, Gao YT, Li C, Cai H, Park SK, Yoo KY, Noh DY, Han W, Dunning AM, Benitez J, Vincent D, Bacot F, Tessier D, Kim SW, Lee MH, Lee JW, Lee JY, Xiang YB, Zheng Y, Wang W, Ji BT, Matsuo K, Ito H, Iwata H, Tanaka H, Wu AH, Tseng CC, Van Den Berg D, Stram DO, Teo SH, Yip CH, Kang IN, Wong TY, Shen CY, Yu JC, Huang CS, Hou MF, Hartman M, Miao H, Lee SC, Putti TC, Muir K, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Sangrajrang S, Shen H, Chen K, Wu PE, Ren Z, Haiman CA, Sueta A, Kim MK, Khoo US, Iwasaki M, Pharoah PD, Wen W, Hall P, Shu XO, Easton DF, Kang D
Source: Hum Mol Genet, 2013 Jun 15;22(12), p. 2539-50.
EPub date: 2013 Mar 27.
PMID: 23535825
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A common deletion in the APOBEC3 genes and breast cancer risk.
Authors: Long J, Delahanty RJ, Li G, Gao YT, Lu W, Cai Q, Xiang YB, Li C, Ji BT, Zheng Y, Ali S, Shu XO, Zheng W
Source: J Natl Cancer Inst, 2013 Apr 17;105(8), p. 573-9.
EPub date: 2013 Feb 14.
PMID: 23411593
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Steps to ensure accuracy in genotype and SNP calling from Illumina sequencing data.
Authors: Liu Q, Guo Y, Li J, Long J, Zhang B, Shyr Y
Source: BMC Genomics, 2012;13 Suppl 8, p. S8.
EPub date: 2012 Dec 17.
PMID: 23281772
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Exome sequencing generates high quality data in non-target regions.
Authors: Guo Y, Long J, He J, Li CI, Cai Q, Shu XO, Zheng W, Li C
Source: BMC Genomics, 2012 May 20;13, p. 194.
EPub date: 2012 May 20.
PMID: 22607156
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Genome-wide association study in east Asians identifies novel susceptibility loci for breast cancer.
Authors: Long J, Cai Q, Sung H, Shi J, Zhang B, Choi JY, Wen W, Delahanty RJ, Lu W, Gao YT, Shen H, Park SK, Chen K, Shen CY, Ren Z, Haiman CA, Matsuo K, Kim MK, Khoo US, Iwasaki M, Zheng Y, Xiang YB, Gu K, Rothman N, Wang W, Hu Z, Liu Y, Yoo KY, Noh DY, Han BG, Lee MH, Zheng H, Zhang L, Wu PE, Shieh YL, Chan SY, Wang S, Xie X, Kim SW, Henderson BE, Le Marchand L, Ito H, Kasuga Y, Ahn SH, Kang HS, Chan KY, Iwata H, Tsugane S, Li C, Shu XO, Kang DH, Zheng W
Source: PLoS Genet, 2012;8(2), p. e1002532.
EPub date: 2012 Feb 23.
PMID: 22383897
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Evaluation of breast cancer susceptibility loci in Chinese women.
Authors: Long J, Shu XO, Cai Q, Gao YT, Zheng Y, Li G, Li C, Gu K, Wen W, Xiang YB, Lu W, Zheng W
Source: Cancer Epidemiol Biomarkers Prev, 2010 Sep;19(9), p. 2357-65.
EPub date: 2010 Aug 10.
PMID: 20699374
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