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Grant Details

Grant Number: 1R01CA202981-01 Interpret this number
Primary Investigator: Zheng, Wei
Organization: Vanderbilt University Medical Center
Project Title: Breast Cancer Genetic Study in African-Ancestry Populations
Fiscal Year: 2016


Abstract

¿ DESCRIPTION (provided by applicant): Breast cancer is the most commonly diagnosed malignancy in the United States. The age-adjusted mortality rate of this cancer is more than 40% higher in African Americans (AAs) than in whites for reasons poorly understood. Since 2007, genome-wide association studies (GWAS) conducted in Asian and European descendants have identified nearly 100 susceptibility loci for this cancer. However, only a few of the initially identified risk variants can be directly replicated in AAs due to a small sample sizein previous studies and racial differences in genetic architectures and genetic/environmental modifiers. GWAS are often not equipped to study structural variants and are inefficient for capturing low-frequency variants. These variants, although virtually uninvestigated to date, are believed to contribute substantially to the heritability of breast cancer and other complex traits, particularly in African-ancestry populations. Furthermore, compared with Asian- and European-ancestry populations, the African-ancestry genome is much more heterogeneous and thus more informative, particularly as we expand the scope of genetic studies from common to less-common variants using next-generation sequencing technology. Herein, we propose a large consortium study in AAs to systematically search the whole genome to discover novel genetic susceptibility factors for breast cancer and further evaluate the influence of germline risk variants on breast cancer biology. Nearly 20,000 AA breast cancer patients and an equal number of controls will be included in this study. In Stage 1, we propose to sequence the whole genome for 1,200 breast cancer cases and 600 controls for association analyses. We will then use these sequencing data, along with data from other sources, to build a novel, comprehensive reference panel for imputation and meta-analysis of approximately 6,300 cases and 6,300 controls genotyped in four previous GWAS conducted in African-ancestry populations. We will utilize publically available genetic data, including functional genomic data, to enhance the abilit of the two aforementioned analyses to identify promising breast cancer susceptibility genes and variants for replication. In Stage 2, we will replicate approximately 60,000 promising variants in 5,500 cases and 5,500 controls. Genes/variants which show a promising association in Stage 2 will be evaluated further in Stage 3, including two additional stages (3A and 3B) in approximately 7,500 cases and 7,500 controls. Finally, we will use gene expression signatures to evaluate how germline risk variants identified in this study and previous studies affect the major signaling pathways of breast cancer. This proposed study will generate critically needed data in AAs to improve the understanding of the genetics, biology, and etiology of breast cancer.



Publications

Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants that Confer Risk for Breast Cancer.
Authors: Sun X. , Verma S.P. , Jia G. , Wang X. , Ping J. , Guo X. , Shu X.O. , Chen J. , Derkach A. , Cai Q. , et al. .
Source: Cancer Research, 2024-06-04 00:00:00.0; , .
EPub date: 2024-06-04 00:00:00.0.
PMID: 38832928
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Association of ESR1 germline variants with TP53 somatic variants in breast tumors in a genome-wide study.
Authors: Tjader N.P. , Beer A.J. , Ramroop J. , Tai M.C. , Ping J. , Gandhi T. , Dauch C. , Neuhausen S.L. , Ziv E. , Sotelo N. , et al. .
Source: Cancer Research Communications, 2024-05-28 00:00:00.0; , .
EPub date: 2024-05-28 00:00:00.0.
PMID: 38836758
Related Citations

Large-scale alternative polyadenylation-wide association studies to identify putative cancer susceptibility genes.
Authors: Guo X. , Ping J. , Yang Y. , Su X. , Shu X.O. , Wen W. , Chen Z. , Zhang Y. , Tao R. , Jia G. , et al. .
Source: Cancer Research, 2024-05-17 00:00:00.0; , .
EPub date: 2024-05-17 00:00:00.0.
PMID: 38759092
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Using genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes.
Authors: Ping J. , Jia G. , Cai Q. , Guo X. , Tao R. , Ambrosone C. , Huo D. , Ambs S. , Barnard M.E. , Chen Y. , et al. .
Source: Nature Communications, 2024-05-02 00:00:00.0; 15(1), p. 3718.
EPub date: 2024-05-02 00:00:00.0.
PMID: 38697998
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Genome-wide association analyses of breast cancer in women of African ancestry identify new susceptibility loci and improve risk prediction.
Authors: Jia G. , Ping J. , Guo X. , Yang Y. , Tao R. , Li B. , Ambs S. , Barnard M.E. , Chen Y. , Garcia-Closas M. , et al. .
Source: Nature Genetics, 2024 May; 56(5), p. 819-826.
EPub date: 2024-05-13 00:00:00.0.
PMID: 38741014
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Addition of polygenic risk score to a risk calculator for prediction of breast cancer in US Black women.
Authors: Zirpoli G.R. , Pfeiffer R.M. , Bertrand K.A. , Huo D. , Lunetta K.L. , Palmer J.R. .
Source: Breast Cancer Research : Bcr, 2024-01-02 00:00:00.0; 26(1), p. 2.
EPub date: 2024-01-02 00:00:00.0.
PMID: 38167144
Related Citations

Association of ESR1 germline variants with TP53 somatic variants in breast tumors in a genome-wide study.
Authors: Tjader N.P. , Beer A.J. , Ramroop J. , Tai M.C. , Ping J. , Gandhi T. , Dauch C. , Neuhausen S.L. , Ziv E. , Sotelo N. , et al. .
Source: Medrxiv : The Preprint Server For Health Sciences, 2023-12-06 00:00:00.0; , .
EPub date: 2023-12-06 00:00:00.0.
PMID: 38106140
Related Citations

Identification of target proteins for breast cancer genetic risk loci and blood risk biomarkers in a large study by integrating genomic and proteomic data.
Authors: Jia G. , Yang Y. , Ping J. , Xu S. , Liu L. , Guo X. , Tao R. , Long J. , Zheng W. .
Source: International Journal Of Cancer, 2023-02-13 00:00:00.0; , .
EPub date: 2023-02-13 00:00:00.0.
PMID: 36779764
Related Citations

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
Related Citations

Associations between circulating proteins and risk of breast cancer by intrinsic subtypes: a Mendelian randomisation analysis.
Authors: Shu X. , Zhou Q. , Sun X. , Flesaker M. , Guo X. , Long J. , Robson M.E. , Shu X.O. , Zheng W. , Bernstein J.L. .
Source: British Journal Of Cancer, 2022-07-26 00:00:00.0; , .
EPub date: 2022-07-26 00:00:00.0.
PMID: 35882941
Related Citations

Evaluating breast cancer predisposition genes in women of African ancestry.
Authors: Díaz-Zabala H. , Guo X. , Ping J. , Wen W. , Shu X.O. , Long J. , Lipworth L. , Li B. , Fadden M.K. , Pal T. , et al. .
Source: Genetics In Medicine : Official Journal Of The American College Of Medical Genetics, 2022 07; 24(7), p. 1468-1475.
EPub date: 2022-04-08 00:00:00.0.
PMID: 35396981
Related Citations

Polygenic Risk Scores for Prediction of Breast Cancer Risk in Women of African Ancestry: a Cross-Ancestry Approach.
Authors: Gao G. , Zhao F. , Ahearn T.U. , Lunetta K.L. , Troester M.A. , Du Z. , Ogundiran T.O. , Ojengbede O. , Blot W. , Nathanson K.L. , et al. .
Source: Human Molecular Genetics, 2022-05-12 00:00:00.0; , .
EPub date: 2022-05-12 00:00:00.0.
PMID: 35554533
Related Citations

A pooled case-only analysis of obesity and breast cancer subtype among Black women in the southeastern United States.
Authors: Moore J. , Pal T. , Beeghly-Fadiel A. , Fadden M.K. , Munro H.M. , Dujon S.A. , Reid S. , Tezak A. , Blasingame M. , Ware J. , et al. .
Source: Cancer Causes & Control : Ccc, 2022-01-28 00:00:00.0; , .
EPub date: 2022-01-28 00:00:00.0.
PMID: 35088206
Related Citations

Discovery of structural deletions in breast cancer predisposition genes using whole genome sequencing data from > 2000 women of African-ancestry.
Authors: Chen Z. , Guo X. , Long J. , Ping J. , Li B. , Fadden M.K. , Ahearn T.U. , Stram D.O. , Shu X.O. , Jia G. , et al. .
Source: Human Genetics, 2021-08-27 00:00:00.0; , .
EPub date: 2021-08-27 00:00:00.0.
PMID: 34487234
Related Citations

Large trans-ethnic meta-analysis identifies AKR1C4 as a novel gene associated with age at menarche.
Authors: Sarnowski C. , Cousminer D.L. , Franceschini N. , Raffield L.M. , Jia G. , Fernández-Rhodes L. , Grant S.F.A. , Hakonarson H. , Lange L.A. , Long J. , et al. .
Source: Human Reproduction (oxford, England), 2021-06-18 00:00:00.0; 36(7), p. 1999-2010.
PMID: 34021356
Related Citations

A pooled case-only analysis of reproductive risk factors and breast cancer subtype among black women in the Southeastern United States.
Authors: Sanderson M. , Pal T. , Beeghly-Fadiel A. , Fadden M.K. , Dujon S.A. , Clinton C. , Jimenez C. , Davis J. , Fortune M. , Thompson J. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2021-05-04 00:00:00.0; , .
EPub date: 2021-05-04 00:00:00.0.
PMID: 33947654
Related Citations

Differences in Gene-Expression Profiles in Breast Cancer between African and European-ancestry Women.
Authors: Ping J. , Guo X. , Ye F. , Long J. , Lipworth L. , Cai Q. , Blot W. , Shu X.O. , Zheng W. .
Source: Carcinogenesis, 2020-04-08 00:00:00.0; , .
EPub date: 2020-04-08 00:00:00.0.
PMID: 32267939
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