PROJECT SUMMARY (tech abs) Even with the typical delays in diagnosis, more advanced stage distribution at diagnosis, and inadequate multidisciplinary breast cancer treatment, these combined factors do not completely explain disparities in breast cancer mortality outcomes, which persist after controlling for stage at diagnosis – and have been so for the past 50 years. The approximately two-fold increased risk of TNBC in AA women has been confirmed by population-based incidence rates regionally as well as nationally and across all age intervals. Compared to non-TNBC, triple negative disease has been confirmed to be an adverse prognostic feature in AA patients, driving some of the mortality disparities. We hypothesize that altered mechanisms of tumor immune responses, which underlies TNBC tumor biology differences between SRR, are caused by population-private genetic variants among individuals with shared west African ancestry. These evolutionarily selected variants alter immune cell behavior and inflammatory mechanisms, leading to novel tumor-immune cell types and significant differences in leukocyte infiltration patterns, which may be associated with poor outcomes. We will perform an innovative multiomics investigation of African-specific gene expression in TNBC, linked to immunological tumor phenotypes. We will harness the novelty of rarely-investigated breast cancer patient populations from diverse African regions with TNBC cases from g admixed populations (i.e. African-American and Afro-Caribbean). The most impactful innovation of this study is the characterization of differential gene expression, coupled with integrated proteomics data, to identify novel tumor phenotypes that are shared among women of the African diaspora. This work will be transformative to our understanding of tumor heterogeneity and biological diversity across patient groups. We propose the follow aims: 1- Determine the ancestry- associated differential gene expression profiles of immune and inflammatory-related genes in primary tumors across an African-enriched cohort of 400 clinically annotated TNBC cases, to immune profiles linked to shared west African genetic ancestry. 2- Characterize ancestry-associated differences in pathological tumor immune response characteristics, including differences in tumor inflammation and/or tumor infiltration of specific immune cell types. 3-Create an African-enriched panel of ex vivo models to validate/investigate the ancestry-associated drivers of altered genetic pathways and immune responses. By completing these aims we expect to yield an African-enriched set of population-private, validated eQTLs, associated with TNBC immune response mechanisms that can be further interrogated by our authenticated ex vivo models.

PROJECT NARRATIVE (lay abs) The mortality gap between African Americans and Whites with breast cancer in the US reflected the unmasking of differences in the biology of breast cancer between AA and WA women related to targeted therapies. Our previous findings implicated African alleles of the DARC gene in etiology of breast cancer phenotypes and its tumor expression with survival, suggesting ancestry-related differences in tumor immunological responses that may stratify patients for improved use of immunotherapy treatments to decrease tumor-subtype-related disparities in mortality. Our proposed work will define the clinical associations of DARC in African breast cancer patients and “DARC tumor” characteristics that will give insight to shared genetic risk among women of the African diaspora who share unique burdens of aggressive breast tumor phenotypes.