Compared to European American men (EAM), African American men (AAM) have 2-3 times higher prostate cancer (PCa) mortality rates. AAM diagnose with more aggressive PCa at an earlier age & clinically advanced disease compared to EAM. Studies suggested that tumor biology & cellular heterogeneity/gene profile, have a potential contribution to racial differences, which remain even when controlled for access to care and stage at presentation. Moreover, men of African ancestry from the Caribbean & South America experience incidence & mortality rates similar to AAM, suggesting a possible ancestral basis for some of these expected outcomes. Additionally, the association of the genomic findings with patient ancestry and with other characteristics such as tumor biology & transcriptomic alterations remains poorly understood. Here we hypothesize that African ancestry drives aggressive prostate cancer and leads to genetic alterations with upregulation of unique Immune-inflammatory signature in AAM of African descent. To assess our hypothesis, we performed genome-wide sequencing (WES & RNA Seq), for a total of (n= 72) patients obtained from treatment-naive PCa who self-reported their race. Out of those 72 samples, 47 samples RNA Seq match with WES. To verify the self-reported race, we used ADMIXTURE to generate a quantitative estimate of each individual ancestral composition. Most of our cohorts who self-reported as AAM, their ancestry assigned to African Ancestry (Ancestry proportion > 70%) with either Bantu subpopulation in Sub-Saharan area and/or Yoruba (Nigeria) subpopulation. Descriptive statistical analyses of the study population were conducted and stratified by race & pathology stage. Our results showed that AA men are diagnosed with PCa at a younger age and higher pathology stage. We ran differential gene expression (DGEs) using EdgR/DESeq2 and enriched pathways based on the patient's ancestry/race using GSEA & EdgR gene ontology function. Our DGEs analyses revealed that gene sets such as activation of the innate immune system and immune-inflammation pathway, as well as interleukin signaling, are positively enriched (p-value 0.05), while gene sets such as RNA Polymerase II transcription and metabolisms signaling are negatively enriched (p-value 0.05) in AAM. Moreover, our WES analysis showed that patients with high African Ancestry associated with AR-related mutation such as FOXA1, PTEN, TP53, EPHB2 with SPOP mutation (18% in AAM vs 8% in EAM) on top of these mutations. Interestingly, when we stratified patients based on PD-L1 expression, AAM with high PD-L1 (Immunogenic) has higher CD8+ T cells/PD-1+ expression than AAM patients with low PD-L1 (Non-Immunogenic). WES analysis showed that AAM with high PD-L1 express SPOP mutation. Our study's findings could lead to new therapeutic strategies using anti-inflammatory drugs and immune modulators to decrease the disease burden among men at high risk for PCa.

Citation Format: Isra A. Elhussin, Jason White, Tiffany Dorsey, Moray J. Campbell, Melissa B. Davis, Stefan Ambs, Isaac Kim, Clayton Yates. Genomic comparison between African American men & European American men with prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1167.