Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes

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

Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes

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

Additional file 13: Movie 8. of In vivo imaging of epithelial wound healing in the cnidarian Clytia hemisphaerica demonstrates early evolution of purse string and cell crawling closure mechanisms

Healing of an epithelial wound where there is a visible tear in the basement membrane (arrow heads). Lamellipodia can be seen to migrate over the area of the wound where the basement membrane is intact (right hand side), but only small finger-like projections are seen in the area that is denuded of the basement membrane. Once lamellipodia meet, the remainder of wound healing appears to occur primarily through a purse string closure mechanism. Frames were taken every 12–13 s. The duration of the movie is 32 min. Scale bar = 50 μm. (MP4 18,233 kb

Additional file 2: Movie 2. of In vivo imaging of epithelial wound healing in the cnidarian Clytia hemisphaerica demonstrates early evolution of purse string and cell crawling closure mechanisms

Wound healing time lapse of the wound pictured in Fig. 3a–f. The major events during each of the phases, as described in the text, are labeled. Frames were taken every 12–13 s. The duration of the movie is 55 min. Scale bar = 50 μm. (MP4 27,840 kb

Additional file 12: Movie 7. of In vivo imaging of epithelial wound healing in the cnidarian Clytia hemisphaerica demonstrates early evolution of purse string and cell crawling closure mechanisms

Lamellipodia-mediated closure of a wound of the same approximate size and shape as in Additional File 11, as shown in Fig. 7F–H. Note that after lamellipodia meet to close the gap, there is a contraction around the perimeter. When looking at a healing wound in this contracted state it is impossible to tell whether the wound originally closed through lamellipodia meeting (this movie) or a purse string drawing the cells forward (Additional file 11). Frames were taken every 12–13 s. The duration of the movie is 10 min. Scale bar = 50 μm. (MP4 5766 kb

Additional file 3: Figure S1. of In vivo imaging of epithelial wound healing in the cnidarian Clytia hemisphaerica demonstrates early evolution of purse string and cell crawling closure mechanisms

Labeling index of cells in the exumbrella. EdU incorporation showed that in the first 3–4 days after release there is very little, if any, division in epithelial cells in the exumbrella. In contrast, at 7 days the percentage of cells dividing within a 24 h period is >40%. By two and three weeks, the number of dividing cells per 24 h is greatly reduced, and declines further as animals age. Therefore, in the 2–3 week old animals used in wounding assays there is little epithelial cell division in the exumbrella. Animals were labelled for 24 h with EdU, and then fixed and stained with Hoescht stain. Values are the percentage of Hoechst stained cells that also showed EdU labeling. 3–5 animals were examined at each time point. Error bars = s.e.m. (PPTX 53 kb

Additional file 5: Movie S1. of In vivo imaging of epithelial wound healing in the cnidarian Clytia hemisphaerica demonstrates early evolution of purse string and cell crawling closure mechanisms

Wound healing time-lapse in the presence of hydroxyurea at concentrations shown to completely inhibit cell division (Additional file 4). Frames were taken every 12–13 s. The duration of the movie is 11 min. Scale bar = 50 μm. (MP4 11,528 kb

De l'importance et de la nécessité des semis pour l'amélioration et le renouvellement des variétés cultivées / par M.-A. Puvis,...

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