Grant Number:	5R01CA202981-07 Interpret this number
Primary Investigator:	Zheng, Wei
Organization:	Vanderbilt University Medical Center
Project Title:	African-Ancestry Breast Cancer Genetic Consortium
Fiscal Year:	2026

PROJECT SUMMARY Breast cancer is the most diagnosed malignancy in the United States. Genetic factors play an important role in breast cancer etiology, but known genetic factors explain only a small fraction of breast cancer heritability, particularly in women of African ancestry (AA). In collaboration with investigators from >25 studies we established the African-ancestry Breast Cancer Genetic Consortium (AABCG) in 2016 to address a significant racial disparity in breast cancer genetic research that includes primarily women of European ancestry (EUR). In AABCG, we conducted genome-wide association studies (GWAS) and related analyses using data from ~18,000 breast cancer cases and ~22,000 controls and reported significant novel findings to begin filling knowledge gaps. By analyzing whole genome sequencing (WGS) data from a smaller number of AA women (~1,340 cases and ~670 controls), we provided promising preliminary data in strong support of the important role of structural variants (SV) and low-frequency and rare single nucleotide variants (SNV) in the etiology of breast cancer. In this competitive renewal application, we propose a large study including both AA and EUR women with a major focus on investigating SVs and low-frequency/rare SNV that carry larger effects than common variants but cannot be adequately studied in GWAS. We plan to expand the AABCG by conducting deep whole genome sequencing (WGS) in 8,000 AA breast cancer cases and harmonize existing WGS data from other studies, which will allow us to expand the AABCG’s sample size to approximately 13,800 AA breast cancer cases and ~80,400 AA controls with deep WGS data. We also will harmonize existing WGS data from several studies to build a resource containing WGS data from ~27,400 EUR cases and ~534,200 EUR controls. Using these data, we propose to 1) systematically evaluate low frequency and rare variants, including both coding and non-coding variants, across the genome to identify novel breast cancer susceptibility variants and genes, and 2) search the whole genome to identify SVs (both common and rare) associated with breast cancer risk. We will also evaluate racial differences in the frequency and type of breast cancer associated SNVs and SVs and the strength of their associations with breast cancer risk. This study will be built upon the success of the AABCG and leverage large amounts of existing data to substantially enhance the national resources for genetic research of breast cancer in an extremely cost-efficient manner. With strong methodology and unique data sources, this study will generate critically needed data that will improve the understanding of breast cancer genetics, biology, and etiology. This will, in turn, facilitate the translation of genetic findings to cancer prevention and treatment.




Multi-ancestry transcriptome-wide association studies uncover insights into breast cancer genetics and biology.
Authors: Ping J. , Jia G. , Cai Q. , Guo X. , Wang J. , Tao R. , Li B. , Bauer J.A. , Xie Y. , Ambs S. , et al. .
Source: Nature Communications, 2026-05-30 00:00:00.0; , .
EPub date: 2026-05-30 00:00:00.0.
PMID: 42218145
Related Citations

African ancestry and risk variants associated with triple-negative breast cancer susceptibility in African American women.
Authors: Jia G. , Liu L. , Ping J. , Fiorica P.N. , Guo X. , Tao R. , Li B. , Gu J. , John E.M. , Olopade O.I. , et al. .
Source: Genome Medicine, 2026-05-07 00:00:00.0; , .
EPub date: 2026-05-07 00:00:00.0.
PMID: 42098873
Related Citations

Association of gene variant type and location with breast cancer risk in the general population.
Authors: Akamandisa M.P. , Boddicker N.J. , Yadav S. , Hu C. , Hart S.N. , Ambrosone C.B. , Anton-Culver H. , Auer P.L. , Bodelon C. , Burnside E.S. , et al. .
Source: Annals Of Oncology : Official Journal Of The European Society For Medical Oncology, 2025 Aug; 36(8), p. 954-963.
EPub date: 2025-04-25 00:00:00.0.
PMID: 40288678
Related Citations

Integrating multi-ancestry genomic and proteomic data to identify blood risk biomarkers and target proteins for breast cancer genetic risk loci.
Authors: Jia G. , Ping J. , Tao R. , Long J. , Liu L. , Xu S. , Munro H.M. , Ambs S. , Barnard M.E. , Chen Y. , et al. .
Source: International Journal Of Cancer, 2025-07-14 00:00:00.0; , .
EPub date: 2025-07-14 00:00:00.0.
PMID: 40658085
Related Citations

The African-specific variant in the Duffy Antigen Receptor for Chemokines (DARC) gene, CD8+ T-cell density and Aggressive Breast Cancer Subtypes in Black Women.
Authors: Nair N.M. , Mendicino L. , Fiorica P.N. , Omilian A.R. , Khoury T. , Bshara W. , Bandera E.V. , Hong C.C. , Abdou Y. , Freudenheim J.L. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2025-07-08 00:00:00.0; , .
EPub date: 2025-07-08 00:00:00.0.
PMID: 40627176
Related Citations

Refining breast cancer genetic risk and biology through multi-ancestry fine-mapping analyses of 192 risk regions.
Authors: Jia G. , Chen Z. , Ping J. , Cai Q. , Tao R. , Li C. , Bauer J.A. , Xie Y. , Ambs S. , Barnard M.E. , et al. .
Source: Nature Genetics, 2025-01-03 00:00:00.0; , .
EPub date: 2025-01-03 00:00:00.0.
PMID: 39753771
Related Citations

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
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: 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
Related Citations

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
Related Citations

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
Related Citations

Novel breast cancer susceptibility loci under linkage peaks identified in African ancestry consortia.
Authors: Ochs-Balcom H.M. , Preus L. , Du Z. , Elston R.C. , Teerlink C.C. , Jia G. , Guo X. , Cai Q. , Long J. , Ping J. , et al. .
Source: Human Molecular Genetics, 2024-01-23 00:00:00.0; , .
EPub date: 2024-01-23 00:00:00.0.
PMID: 38263910
Related Citations

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

Associations of genetic susceptibility to 16 cancers with risk of breast cancer overall and by intrinsic subtypes.
Authors: Choi J. , Jia G. , Wen W. , Tao R. , Long J. , Shu X.O. , Zheng W. .
Source: Hgg Advances, 2022-01-13 00:00:00.0; 3(1), p. 100077.
EPub date: 2021-12-10 00:00:00.0.
PMID: 35047862
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

Evaluating Polygenic Risk Scores for Breast Cancer in Women of African Ancestry.
Authors: Du Z. , Gao G. , Adedokun B. , Ahearn T. , Lunetta K.L. , Zirpoli G. , Troester M.A. , Ruiz-Narváez E.A. , Haddad S.A. , Pal Choudhury P. , et al. .
Source: Journal Of The National Cancer Institute, 2021-03-26 00:00:00.0; , .
EPub date: 2021-03-26 00:00:00.0.
PMID: 33769540
Related Citations

Evaluating the Utility of Polygenic Risk Scores in Identifying High-Risk Individuals for Eight Common Cancers.
Authors: Jia G. , Lu Y. , Wen W. , Long J. , Liu Y. , Tao R. , Li B. , Denny J.C. , Shu X.O. , Zheng W. .
Source: Jnci Cancer Spectrum, 2020 Jun; 4(3), p. pkaa021.
EPub date: 2020-03-12 00:00:00.0.
PMID: 32596635
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
Related Citations