From Springer Nature via Jisc Publications RouterHistory: received 2020-12-12, accepted 2021-11-02, registration 2021-11-04, pub-electronic 2021-11-26, online 2021-11-26, collection 2021-12Publication status: PublishedFunder: Postdoctoral Research Fellowship P2BSP3_178591Funder: Francis Crick Institute (Francis Crick Institute Limited); doi: https://doi.org/10.13039/100010438Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289; Grant(s): FC001202Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440; Grant(s): FC001202Funder: U.S. Department of Health & Human Services | National Institutes of Health (NIH); doi: https://doi.org/10.13039/100000002; Grant(s): U01 CA161032, U01 CA161032, R01 MD013452, R01 CA228198, U01 CA161032, R01 MD013452, P20-CA233307Funder: U.S. Department of Health & Human Services | National Institutes of Health (NIH)Funder: Breast Cancer Research Foundation (BCRF); doi: https://doi.org/10.13039/100001006; Grant(s): BCRF-20-071, BCRF-19-120Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272; Grant(s): 203141/Z/16/ZFunder: Susan G. Komen (Susan G. Komen Breast Cancer Foundation); doi: https://doi.org/10.13039/100009634; Grant(s): SAC110026, SAC210203Funder: American Cancer Society (American Cancer Society, Inc.); doi: https://doi.org/10.13039/100000048Abstract: Black women across the African diaspora experience more aggressive breast cancer with higher mortality rates than white women of European ancestry. Although inter-ethnic germline variation is known, differential somatic evolution has not been investigated in detail. Analysis of deep whole genomes of 97 breast cancers, with RNA-seq in a subset, from women in Nigeria in comparison with The Cancer Genome Atlas (n = 76) reveal a higher rate of genomic instability and increased intra-tumoral heterogeneity as well as a unique genomic subtype defined by early clonal GATA3 mutations with a 10.5-year younger age at diagnosis. We also find non-coding mutations in bona fide drivers (ZNF217 and SYPL1) and a previously unreported INDEL signature strongly associated with African ancestry proportion, underscoring the need to expand inclusion of diverse populations in biomedical research. Finally, we demonstrate that characterizing tumors for homologous recombination deficiency has significant clinical relevance in stratifying patients for potentially life-saving therapies
