Grant Number:	2R01CA202981-06 Interpret this number
Primary Investigator:	Zheng, Wei
Organization:	Vanderbilt University Medical Center
Project Title:	African-Ancestry Breast Cancer Genetic Consortium
Fiscal Year:	2025

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.





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