Grant Number:	1R01CA137013-01A1 Interpret this number
Primary Investigator:	Long, Jirong
Organization:	Vanderbilt University
Project Title:	Genome-Wide Copy Number Variation and Breast Cancer Risk
Fiscal Year:	2009

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.




Genome- and transcriptome-wide association studies of 386,000 Asian and European-ancestry women provide new insights into breast cancer genetics.
Authors: Jia G. , Ping J. , Shu X. , Yang Y. , Cai Q. , Kweon S.S. , Choi J.Y. , Kubo M. , Park S.K. , Bolla M.K. , et al. .
Source: American Journal Of Human Genetics, 2022-11-03 00:00:00.0; , .
EPub date: 2022-11-03 00:00:00.0.
PMID: 36356581
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Identification of novel breast cancer susceptibility loci in meta-analyses conducted among Asian and European descendants.
Authors: Shu X. , Long J. , Cai Q. , Kweon S.S. , Choi J.Y. , Kubo M. , Park S.K. , Bolla M.K. , Dennis J. , Wang Q. , et al. .
Source: Nature Communications, 2020-03-05 00:00:00.0; 11(1), p. 1217.
EPub date: 2020-03-05 00:00:00.0.
PMID: 32139696
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Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels.
Authors: Spracklen C.N. , Chen P. , Kim Y.J. , Wang X. , Cai H. , Li S. , Long J. , Wu Y. , Wang Y.X. , Takeuchi F. , et al. .
Source: Human Molecular Genetics, 2017-05-01 00:00:00.0; 26(9), p. 1770-1784.
PMID: 28334899
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Prediction Of Breast Cancer Risk Based On Common Genetic Variants In Women Of East Asian Ancestry
Authors: Wen W. , Shu X.O. , Guo X. , Cai Q. , Long J. , Bolla M.K. , Michailidou K. , Dennis J. , Wang Q. , Gao Y.T. , et al. .
Source: Breast Cancer Research : Bcr, 2016-12-08 00:00:00.0; 18(1), p. 124.
PMID: 27931260
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Age At Menarche And Age At Natural Menopause In East Asian Women: A Genome-wide Association Study
Authors: Shi J. , Zhang B. , Choi J.Y. , Gao Y.T. , Li H. , Lu W. , Long J. , Kang D. , Xiang Y.B. , Wen W. , et al. .
Source: Age (dordrecht, Netherlands), 2016 Dec; 38(5-6), p. 513-523.
PMID: 27629107
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Long Intergenic Non-coding Rna Expression Signature In Human Breast Cancer
Authors: Zhang Y. , Wagner E.K. , Guo X. , May I. , Cai Q. , Zheng W. , He C. , Long J. .
Source: Scientific Reports, 2016-11-29 00:00:00.0; 6, p. 37821.
PMID: 27897201
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Genome-wide Association Study In East Asians Identifies Two Novel Breast Cancer Susceptibility Loci
Authors: Han M.R. , Long J. , Choi J.Y. , Low S.K. , Kweon S.S. , Zheng Y. , Cai Q. , Shi J. , Guo X. , Matsuo K. , et al. .
Source: Human Molecular Genetics, 2016-08-01 00:00:00.0; 25(15), p. 3361-3371.
PMID: 27354352
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Integrative genomic analysis reveals functional diversification of APOBEC gene family in breast cancer.
Authors: Zhang Y. , Delahanty R. , Guo X. , Zheng W. , Long J. .
Source: Human Genomics, 2015-12-18 00:00:00.0; 9, p. 34.
EPub date: 2015-12-18 00:00:00.0.
PMID: 26682542
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Genome-wide association meta-analysis identifies novel variants associated with fasting plasma glucose in East Asians.
Authors: Hwang J.Y. , Sim X. , Wu Y. , Liang J. , Tabara Y. , Hu C. , Hara K. , Tam C.H. , Cai Q. , Zhao Q. , et al. .
Source: Diabetes, 2015 Jan; 64(1), p. 291-8.
PMID: 25187374
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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 S.K. , Kweon S.S. , Lu W. , Shi J. , Long J. , Wen W. , Choi J.Y. , et al. .
Source: Nature Genetics, 2014 Aug; 46(8), p. 886-90.
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 X.O. , Cai Q. , Zheng Y. , Li C. , Li B. , Gao Y.T. , Zheng W. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2014 Apr; 23(4), p. 622-8.
PMID: 24470074
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Improved variant calling accuracy by merging replicates in whole-exome sequencing studies.
Authors: Zhang Y. , Li B. , Li C. , Cai Q. , Zheng W. , Long J. .
Source: Biomed Research International, 2014; 2014, p. 319534.
PMID: 25162009
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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 J.Y. , Xiang Y.B. , Kim M.K. , Iwasaki M. , Long J. , Ji B.T. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2013 Jul; 22(7), p. 1297-303.
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 J.Y. , Long J. , Dennis J. , Humphreys M.K. , et al. .
Source: Human Molecular Genetics, 2013-06-15 00:00:00.0; 22(12), p. 2539-50.
EPub date: 2013-06-15 00:00:00.0.
PMID: 23535825
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A common deletion in the APOBEC3 genes and breast cancer risk.
Authors: Long J. , Delahanty R.J. , Li G. , Gao Y.T. , Lu W. , Cai Q. , Xiang Y.B. , Li C. , Ji B.T. , Zheng Y. , et al. .
Source: Journal Of The National Cancer Institute, 2013-04-17 00:00:00.0; 105(8), p. 573-9.
EPub date: 2013-04-17 00:00:00.0.
PMID: 23411593
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Exome sequencing generates high quality data in non-target regions.
Authors: Guo Y. , Long J. , He J. , Li C.I. , Cai Q. , Shu X.O. , Zheng W. , Li C. .
Source: Bmc Genomics, 2012-05-20 00:00:00.0; 13, p. 194.
EPub date: 2012-05-20 00:00:00.0.
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 J.Y. , Wen W. , Delahanty R.J. , Lu W. , Gao Y.T. , et al. .
Source: Plos Genetics, 2012; 8(2), p. e1002532.
PMID: 22383897
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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.
PMID: 23281772
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Evaluation of breast cancer susceptibility loci in Chinese women.
Authors: Long J. , Shu X.O. , Cai Q. , Gao Y.T. , Zheng Y. , Li G. , Li C. , Gu K. , Wen W. , Xiang Y.B. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2010 Sep; 19(9), p. 2357-65.
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