Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes
Naser Ansari‐Pour, Yonglan Zheng, Toshio F. Yoshimatsu, Ayodele Sanni, Mustapha Ajani, J.-P. de Reynier, Avraam Tapinos, Jason J. Pitt, Stefan C. Dentro, Anna Woodard, Padma Sheila Rajagopal, Dominic Fitzgerald, Andreas Gruber, Abayomi Odetunde, Abiodun Popoola, Adeyinka G. Falusi, Chinedum P. Babalola, Temidayo O. Ogundiran, Nasiru Ibrahim, Jordi Barretina, Peter Van Loo, Mengjie Chen, Kevin P. White, Oladosu Ojengbede, John Obafunwa, Dezheng Huo, David C. Wedge, Olufunmilayo I. Olopade
Abstract
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.