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 #
5R01CA148667-04
Application #
8610147
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Martin, Damali
Project Start
2011-02-15
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
4
Fiscal Year
2014
Total Cost
$577,558
Indirect Cost
$207,329
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
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(2016) Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus. Nat Commun 7:12675
(2016) Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus. Breast Cancer Res 18:64
(2016) Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170. Nat Genet 48:374-86
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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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