Genome-wide Copy Number Variation and Breast Cancer Risk

Summary

Principal Investigator: Ji Rong Long
Affiliation: Vanderbilt University
Country: USA
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.
Funding Period: 2009-07-01 - 2013-05-31
more information: NIH RePORT

Top Publications

  1. pmc Exome sequencing generates high quality data in non-target regions
    Yan Guo
    Center for Quantitative Sciences, Vanderbilt Ingram Cancer Center, Nashville, TN, USA
    BMC Genomics 13:194. 2012
  2. pmc Steps to ensure accuracy in genotype and SNP calling from Illumina sequencing data
    Qi Liu
    Center for Quantitative Sciences, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
    BMC Genomics 13:S8. 2012
  3. pmc A common deletion in the APOBEC3 genes and breast cancer risk
    Jirong Long
    Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203 1738, USA
    J Natl Cancer Inst 105:573-9. 2013
  4. pmc Common genetic determinants of breast-cancer risk in East Asian women: a collaborative study of 23 637 breast cancer cases and 25 579 controls
    Wei Zheng
    Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
    Hum Mol Genet 22:2539-50. 2013
  5. pmc New breast cancer risk variant discovered at 10q25 in East Asian women
    Jiajun Shi
    Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
    Cancer Epidemiol Biomarkers Prev 22:1297-303. 2013
  6. pmc Rare coding variants and breast cancer risk: evaluation of susceptibility Loci identified in genome-wide association studies
    Yanfeng Zhang
    Authors Affiliations Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt Ingram Cancer Center Department of Biostatistics Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, Tennessee Shanghai Center for Disease Control and Prevention and Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China
    Cancer Epidemiol Biomarkers Prev 23:622-8. 2014
  7. pmc Evaluation of breast cancer susceptibility loci in Chinese women
    Jirong Long
    Division of Epidemiology, Department ofMedicine, Vanderbilt Epidemiology Center, Vanderbilt Ingram Cancer Center, Nashville, TN 37203 1738, USA
    Cancer Epidemiol Biomarkers Prev 19:2357-65. 2010
  8. pmc Genome-wide association study in east Asians identifies novel susceptibility loci for breast cancer
    Jirong Long
    Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
    PLoS Genet 8:e1002532. 2012

Scientific Experts

  • Wei Zheng
  • Ji Rong Long
  • Xiao Ou Shu
  • Qiuyin Cai
  • Yan Guo
  • Yanfeng Zhang
  • Wei Lu
  • Ying Zheng
  • Yu Tang Gao
  • Chun Li
  • Jiajun Shi
  • Qi Liu
  • Bingshan Li
  • Jong Young Lee
  • Jong Won Lee
  • Keun Young Yoo
  • Sung Won Kim
  • Chen Yang Shen
  • Mi Kyung Kim
  • Wonshik Han
  • Shoichiro Tsugane
  • Yong Bing Xiang
  • Ben Zhang
  • Sue K Park
  • Bu Tian Ji
  • Sei Hyun Ahn
  • Motoki Iwasaki
  • Dong Young Noh
  • Daehee Kang
  • Ji Yeob Choi
  • Wenjing Wang
  • Keitaro Matsuo
  • Min Hyuk Lee
  • Hyuna Sung
  • Bing Zhang
  • Jing He
  • Yu Shyr
  • Jiang Li
  • Chung I Li

Detail Information

Publications8

  1. pmc Exome sequencing generates high quality data in non-target regions
    Yan Guo
    Center for Quantitative Sciences, Vanderbilt Ingram Cancer Center, Nashville, TN, USA
    BMC Genomics 13:194. 2012
    ..A significant amount of DNA fragments from the capture process fall outside target regions, and sequence data for positions outside target regions have been mostly ignored after alignment...
  2. pmc Steps to ensure accuracy in genotype and SNP calling from Illumina sequencing data
    Qi Liu
    Center for Quantitative Sciences, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
    BMC Genomics 13:S8. 2012
    ..In this study, we made a systematic assessment of the relative contribution of each step to the accuracy of variant calling from Illumina DNA sequencing data...
  3. pmc A common deletion in the APOBEC3 genes and breast cancer risk
    Jirong Long
    Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203 1738, USA
    J Natl Cancer Inst 105:573-9. 2013
    ..However, these loci explain only a small fraction of the heritability. Very few studies have evaluated copy number variation (CNV), another important source of human genetic variation, in relation to breast cancer risk...
  4. pmc Common genetic determinants of breast-cancer risk in East Asian women: a collaborative study of 23 637 breast cancer cases and 25 579 controls
    Wei Zheng
    Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
    Hum Mol Genet 22:2539-50. 2013
    ..Taken together, these common genetic risk variants explain ~10% of excess familial risk of breast cancer in Asian populations...
  5. pmc New breast cancer risk variant discovered at 10q25 in East Asian women
    Jiajun Shi
    Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
    Cancer Epidemiol Biomarkers Prev 22:1297-303. 2013
    ..Most of these risk variants have not been directly replicated in Asian populations...
  6. pmc Rare coding variants and breast cancer risk: evaluation of susceptibility Loci identified in genome-wide association studies
    Yanfeng Zhang
    Authors Affiliations Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt Ingram Cancer Center Department of Biostatistics Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, Tennessee Shanghai Center for Disease Control and Prevention and Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China
    Cancer Epidemiol Biomarkers Prev 23:622-8. 2014
    ..To date, common genetic variants in approximately 70 loci have been identified for breast cancer via genome-wide association studies (GWAS). It is unknown whether rare variants in these loci are also associated with breast cancer risk...
  7. pmc Evaluation of breast cancer susceptibility loci in Chinese women
    Jirong Long
    Division of Epidemiology, Department ofMedicine, Vanderbilt Epidemiology Center, Vanderbilt Ingram Cancer Center, Nashville, TN 37203 1738, USA
    Cancer Epidemiol Biomarkers Prev 19:2357-65. 2010
    ..Recent genome-wide association studies (GWAS), mostly conducted among women of European ancestry, have identified 16 single-nucleotide polymorphisms (SNP) associated with breast cancer...
  8. pmc Genome-wide association study in east Asians identifies novel susceptibility loci for breast cancer
    Jirong Long
    Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
    PLoS Genet 8:e1002532. 2012
    ..This study provides strong evidence for a novel breast cancer susceptibility locus represented by rs9485372, near the TAB2 gene (6q25.1), and identifies two possible susceptibility loci located in the ESR1 gene and 11q24.3, respectively...