Abstract 750: Ancestry-related differentially spliced and expressed genes in prostate cancer

Abstract

Abstract Prostate cancer (PCa) affects disproportionally men from different population groups. The Surveillance, Epidemiology, and End Results Program’s (SEER’s) 2018 report reveals that PCa incidence and mortality rates are ~2 times higher among African American (AA) men in comparison with white men. In addition to differences in social, lifestyle and structural determinants of health, there is accumulating evidence for a biological contribution to racial disparity in PCa. To date, most work focused on understanding further the molecular mechanisms underlying racial disparity in PCa has analyzed differential aggregate gene expression and mutation among PCa from patients of different population groups. Our recently published work reported alternative RNA splicing (ARS) as a mechanism promoting tumor aggressiveness and drug resistance in PCa from AA patients. Here, we analyzed The Cancer Genome Atlas (TCGA) data using the Genomic Data Commons to analyze differential aggregate gene expression (2-fold mean change, p < 0.001, Wilcoxon rank sum test) and TCGASpliceSeq to analyze ARS (20% median change, percent spliced in) between PCa from AA and white patients. From our analysis of the 307 PCa specimens from white patients and 49 PCa specimens from AA patients, we identified 71 differentially expressed genes (DEGs) and 73 differential RNA splicing events (DRSEs) between PCa from AA and white patients. 51 of the DEGs (~72%) exhibit increased expression levels in PCa from AA patients compared with white patients. Among the DRSEs, the majority involve exon skipping (35 events, ~48%). Notably, the genes that exhibit differential aggregate gene expression and the genes that undergo differential ARS do not overlap, indicating that ancestry-related differences in aggregate gene expression and ARS can be independent events. However, a significant number of the Gene Ontology terms corresponding to the genes exhibiting ancestry-related differential aggregate gene expression or differential ARS do overlap, indicating that, despite these two distinct mechanisms of regulation (transcription and RNA splicing), both differentially regulate common pathways in PCa between AA and white patients. In addition, we identified 10 trans-acting splicing factors (SFs), whose aggregate gene expression significantly differed between PCa from AA and white patients, suggesting a potential mechanistic relationship between these SFs and the identified DRSEs. These findings increase understanding of molecular mechanisms underlying racial disparity in PCa. Upon further study, such DEGs and DRSEs have the potential to be candidates for novel precision medicine interventions. Citation Format: Muthana Al Abo, Daniel J. George, Jennifer A. Freedman, Steven R. Patierno. Ancestry-related differentially spliced and expressed genes in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 750.