Abstract 7467: Multi-omics analysis reveals high chronic inflammation in African Americans compared to Native African Men with prostate cancer

Abstract

Abstract Men of African descent have the highest prostate cancer (PCa) mortality rates in the United States and globally. Studies suggested that tumor subtypes or gene expression profiles had the greatest influence on overall racial/ethnic survival, accounting for 24% of the disparities in PCa and remains even when controlled for access to care and stage at presentation. Moreover, the tumor microenvironment plays an essential role in tumor progression, aggressiveness, therapeutic response, and patient outcomes. Additionally, the association of the genomic findings with patient ancestry and other characteristics, such as tumor biology and transcriptomic alterations, remains poorly understood. Here, we performed a multi-Omics approach (N=447) to unravel the complexity of tumor heterogeneity and understand disease progression & distinct tumor biology influenced by genetic ancestry. We performed Whole Exome (Normal/tumor paired) Sequencing matched with Methyl Seq and Whole transcriptomic Sequencing for three datasets of our African, African American Men (AAM), and European Men (EAM). Additionally, we ran Spatial NanoString high-plex GeoMx-DSP at the protein and RNA levels for a total of 118 treatment-naive PCa patients (around 500 ROIs). Simultaneously, we added matched genome-wide Sequencing (whole transcriptome) for these patients. The cohort comprised 87 AAM, 3 unknown, and 28 EAM self-reported individuals. To verify the self-reported race, the genomic ancestry was qualified using genotype and Admixture analysis. To further validate differentially expressed genes at the protein level, we performed multi-plex histological staining of 40 markers to determine the spatial resolution and neighborhood clustering within the tumor and the microenvironment. In parallel, we performed scMultiOmics sequencing (scRNA & scATAC-Seq) at a single-cell resolution (6000 cells/sample at 25K reads per cell) from an additional 12 patients (9 AAM & 3 EAM). Our results demonstrate that patients who self-report as AAM or Nigerian are assigned to high African (> 70%) Ancestry with either Yoruba (Nigeria) and/or Bantu subpopulation in the Sub-Saharan area. Additionally, high African Ancestry patients are diagnosed at a younger age and show advanced pathology stages compared to patients with European Ancestry. AAM with Yoruba descent express significantly higher immune-inflammatory signatures (IFNG-signaling pathway) compared to the Nigerian-Yoruba subpopulation. Our scRNA-Seq analysis shows that AAM has myeloid cells that infiltrate within the tumor cells. The infiltrations of these cells change with age, Gleason Grade, and pathology stage. Our study provides new insight into how genetic ancestry impacts immune signatures in AAM/African and contributes to PCa racial disparities. Citation Format: Isra Elhussin, Ezra Baraban, Tamara L. Lotan, Cathy Handy Marshall, Emmanuel Antonarakis, Moray J. Campbell, Melissa Davis, Michael Dixon, Isaac Kim, Stefan Ambs, Rick Kittles, Adam B. Murphy, Clayton Yates. Multi-omics analysis reveals high chronic inflammation in African Americans compared to Native African Men with prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7467.