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

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.

Racial Disparities in Pathological Complete Response Among Patients Receiving Neoadjuvant Chemotherapy for Early-Stage Breast Cancer

“…1,2 We and others have previously described overrepresentation of aggressive subtypes as well as differences in the genomic landscape of breast cancer in Black women. [3][4][5][6] However, there is still a paucity of data in non-European ancestry groups to gain a better understanding of the biology and heterogeneity of breast cancer to optimize breast cancer therapies through the implementation of omics-informed oncology care. 7 Biomarker-informed clinical trials in the adjuvant vs neoadjuvant setting have demonstrated benefits of neoadjuvant chemotherapy (NACT) in patients with locally advanced or inoperable breast cancers by downsizing their tumors and increasing the chances of breast-conserving surgery.…”

“…While breast cancer mortality has been decreasing since the 1990s in the US, Canada, and many European countries, mortality rates are rising in many countries in Asia, Latin America and Africa . We and others have previously described overrepresentation of aggressive subtypes as well as differences in the genomic landscape of breast cancer in Black women . However, there is still a paucity of data in non-European ancestry groups to gain a better understanding of the biology and heterogeneity of breast cancer to optimize breast cancer therapies through the implementation of omics-informed oncology care …”

Whole-genome analysis identifies novel drivers and high-risk double-hit events in relapsed/refractory myeloma

“…Leveraging the WGS breadth of our rrMM and ndMM data sets, we sought to identify novel rrMM drivers by detecting differentially enriched somatic noncoding mutational hotspots flanking protein-coding genes (refer to Ansari-Pour et al 33 ). For this analysis, we used a construct similar to that of a genome-wide association study and looked for regions with a higher somatic mutation recurrence in the rrMM data set.…”

Zinc finger and SCAN domain containing 1, ZSCAN1, is a novel stemness-related tumor suppressor and transcriptional repressor in breast cancer targeting TAZ

“…BC is a heterogeneous disease at both molecular and clinical level (2). Usually, BC was divided into luminal, HER2-amplified, and triple-negative/basal cancers (3,4). Luminal BC, the most common subtype, has the best prognosis and benefits from targeted endocrine therapies due to hormone receptor expression.…”