Abstract: Breast cancer is a heterogeneous disease and the incidence to mortality ratio is highest for women of African ancestry. Paucity of data from non-European ancestry groups limits our understanding of the underlying etiological differences or alternative routes to progression that may explain differential outcomes. To examine the contribution of genomic differences, we performed high-depth whole-genome sequencing on 100 breast tumors (90X) and their paired normal samples (30X) from indigenous African women with breast cancer in Southwest Nigeria and performed comparative analysis with 84 TCGA whole genome sequences of breast tumor/normal pairs (46 White, 30 African American and 8 samples representing other ethnicities). High confidence somatic single nucleotide variants (SNVs) were obtained by using MuTect and Strelka. To analyse intra-tumoral heterogeneity (ITH), Battenberg and DPClust were used to call copy number aberrations (CNA) and cluster somatic SNVs based on cancer cell fraction (CCF) respectively. We find that in the HR-/HER2+ subtype, clonal losses of chromosome 14q are highly enriched in Nigerians (41%) but absent in the Whites even though the proportion of this subtype was comparable between the two groups (42% and 33% respectively). This is an interesting observation since not only 14q loss is known to be an event associated with breast cancer aggressiveness, but HR-/HER2+ has also been reported to be enriched within the relatively younger Nigerian patients with breast cancer. This may in part explain inter-ethnic disparity in survival. Also, somatic SNV clustering analysis showed that Nigerian cancers have a higher level of ITH than Whites, which may explain the pronounced aggressiveness of breast cancer in women of African ancestry. In contrast, early drivers (e.g. TP53 and PIK3CA) and whole genome duplication rates were mostly similar between the groups. Our observations suggest differences in the underlying evolutionary trajectories of breast cancer across ethnic backgrounds. These data underscore the need for larger and more in-depth studies of diverse cancer genomes and, if validated, may translate into clinical intervention opportunities tailored to women of African ancestry and accelerate progress in precision cancer care.