African-Ancestry Associated Gene Expression Signatures and Pathways in Triple Negative Breast Cancer, a Comparison across Women of African Descent

Abstract

ABSTRACTWomen of sub-Saharan African ancestry have disproportionately higher incidence of aggressive, early-onset Triple Negative Breast Cancer (TNBC), and TNBC mortality across all race groups. Population-based comparative studies show racial differences in TNBC tumor biology, with higher prevalence of basal-like and Quadruple-Negative subtypes in African Americans (AA). However, most investigations relied on self-reported race (SRR) of primarily United States (US) populations. However, given that genetic admixture in AAs is extremely heterogenous, and race-correlated social determinants can translate into biological differences, the true association of African ancestry with TNBC biology and gene expression is currently unclear. To address this, we conducted RNAseq on an international cohort of AAs, west and east Africans with TNBC. Using genetic ancestry estimation in this African-enriched cohort, we identified 613 genes associated with African ancestry and more than 2200 genes associated with regional-level African ancestry. Functional enrichment and deconvolution revealed tumor-associated immune cell infiltration and activity.STATEMENT OF SIGNIFICANCEUsing a rigorous ancestry quantification process, we show that TNBC has ancestry-associated gene expression profiles, linked to immunological landscapes, which may contribute to racial differences in clinical outcomes. This is the first study to show the definitive link to tumor immunological landscape, associated with African ancestry, using a multiethnic African-enriched cohort.