The DARC side of Breast Cancer Disparities - African Ancestry and Cancer- Related Immune Response

Breast cancer mortality remains disproportionately high in women with triple-negative breast cancer (TNBC), even after accounting for stage at diagnosis and access to treatment. The approximately two-fold increased risk of TNBC among women with West African genetic ancestry has been confirmed across regional and national incidence data and across all age intervals. Compared to other breast cancer subtypes, TNBC has consistently been associated with poorer outcomes, in part due to distinct biological and immunological features. We hypothesize that population-specific genetic variants, enriched in individuals with a genetic ancestry primarily from African descent, contribute to altered tumor-immune interactions in TNBC. These evolutionarily selected variants may influence immune cell behavior and inflammatory pathways, producing novel tumor–immune microenvironments and distinct leukocyte infiltration patterns that impact prognosis. To investigate this, we will perform an integrated multi-omics analysis of population-specific-associated immune gene expression and immunological tumor phenotypes in TNBC. This study leverages rarely investigated patient cohorts from African regions and admixed populations with West African ancestry, including African American and Afro-Caribbean cases. The innovation of this project lies in linking ancestry-associated gene expression with proteomic data to define novel tumor phenotypes and immune response signatures. Specific Aims: 1. Define ancestry-associated gene expression patterns. Determine differential expression profiles of immune- and inflammation-related genes in primary tumors across a clinically annotated cohort of 400 TNBC cases, with a focus on ancestry-associated immune signatures. 2. Characterize tumor immune response phenotypes related with genetic background from west Africa. Identify variation in tumor inflammatory profiles and immune cell infiltration patterns associated with rarely investigated ancestry to define novel biological subtypes of TNBC. This work will advance understanding of tumor heterogeneity and immunological variation in TNBC, improving the accuracy and generalizability of genomic discoveries and informing future approaches to precision oncology.