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. Recent genome-wide association studies (GWAS) have identified multiple genetic susceptibility loci for breast cancer. However, these newly- identified genetic factors, along with high-penetrance susceptibility genes reported previously (such as the BRCA1 and BRCA2 genes), explain only a small fraction of genetic variation for breast cancer. In this application, we propose two novel projects that will significantly advance our understanding of the genetic basis for breast cancer and the methodology used for genetic epidemiologic research. The first project is a GWAS based on the newly-established Asia Breast Cancer Consortium and will include over 27,000 cases and controls recruited from 11 studies conducted among Asian women living in various parts of the world. Through analyzing GWA scan data from 3,500 cases and 3,500 controls, we will identify and evaluate the top 8,500 SNPs in an independent set of 3,500 cases and 3,500 controls and then validate approximately the top 100 SNPs in 6,700 cases and 6,700 controls. In the second project, we will sequence eight GWAS-mapped regions in 3,000 cases and 3,000 controls with the goal of identifying additional genetic risk variants, particularly low- frequency variants, for breast cancer in these regions. We will select up to 180 promising SNPs for replication in an independent set of 2,500 cases and 2,500 controls and then select the top 30 SNPs for further evaluation in another independent set of 2,500 cases and 2,500 controls. This is the only well-powered GWAS conducted in Asian women, and thus is the only existing GWAS capable of discovering genetic variants for breast cancer that are unlikely or more difficult to identify in other GWAS. The proposed sequencing project represents a new model for future genetic association studies. These two newly-proposed projects will be built upon several well- conducted, NCI-funded studies to generate substantial novel information that will help to not only understand breast cancer biology and genetics, but also to improve risk assessment models and identify high-risk women for cost-efficient prevention of breast cancer.

Public Health Relevance

Genetic factors play a major role in the etiology of breast cancers, yet only a small number of cases are explained by genetic factors identified thus far. The large epidemiologic study we propose will comprehensively evaluate genetic markers in relation to breast cancer risk. This study will generate valuable results for the identification of high-risk women for the primary and secondary prevention of breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA148667-02S1
Application #
8520969
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Gillanders, Elizabeth
Project Start
2011-02-15
Project End
2016-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
2
Fiscal Year
2012
Total Cost
$156,000
Indirect Cost
$56,000
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Guo, Xingyi; Lin, Weiqiang; Bao, Jiandong et al. (2018) A Comprehensive cis-eQTL Analysis Revealed Target Genes in Breast Cancer Susceptibility Loci Identified in Genome-wide Association Studies. Am J Hum Genet 102:890-903
Dai, Juncheng; Shen, Wei; Wen, Wanqing et al. (2017) Estimation of heritability for nine common cancers using data from genome-wide association studies in Chinese population. Int J Cancer 140:329-336
Michailidou, Kyriaki (see original citation for additional authors) (2017) Association analysis identifies 65 new breast cancer risk loci. Nature 551:92-94
Han, Mi-Ryung; Zheng, Wei; Cai, Qiuyin et al. (2017) Evaluating genetic variants associated with breast cancer risk in high and moderate-penetrance genes in Asians. Carcinogenesis 38:511-518
Spracklen, Cassandra N; Chen, Peng; Kim, Young Jin et al. (2017) Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels. Hum Mol Genet 26:1770-1784
Milne, Roger L (see original citation for additional authors) (2017) Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer. Nat Genet 49:1767-1778
Shi, Jiajun; Zhang, Ben; Choi, Ji-Yeob et al. (2016) Age at menarche and age at natural menopause in East Asian women: a genome-wide association study. Age (Dordr) 38:513-523
Liu, Jingjing; Lon?ar, Ivona; Collée, J Margriet et al. (2016) rs2735383, located at a microRNA binding site in the 3'UTR of NBS1, is not associated with breast cancer risk. Sci Rep 6:36874
Luu, Hung N; Long, Jirong; Wen, Wanqing et al. (2016) Association between genetic risk score for telomere length and risk of breast cancer. Cancer Causes Control 27:1219-28
Darabi, Hatef; Beesley, Jonathan; Droit, Arnaud et al. (2016) Fine scale mapping of the 17q22 breast cancer locus using dense SNPs, genotyped within the Collaborative Oncological Gene-Environment Study (COGs). Sci Rep 6:32512

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