Abstract A001: Differential alternative RNA splicing and transcription events between Black and White prostate cancer patients involve genes promoting cancer aggressiveness and associate with patient survival

Abstract

Abstract Black patients suffer disproportionately from prostate cancer (PCa) progression to lethal disease compared with Asian and White patients. Comparing the molecular landscape of PCa in Black and White men has the potential to identify targets for development of new precision medicine interventions. Alternative RNA splicing and transcription events (ARS/Ts) can alter gene function. Cancer may exploit ARS/Ts to enhance proliferation, metastasis, and drug resistance. Here, we isolated RNA from fresh frozen PCa specimens and tumor-associated normal (TAN) specimens from 35 self-reported Black and 37 self-reported White patients diagnosed with Gleason-high or -low PCa and undergoing radical prostatectomy or biopsy. Analysis of follow-up clinical data for patients participating in our study show an increased hazard ratio of PCa progression among Black patients compared to White patients (HR = 2.13 and p < 0.05). We performed comparative transcriptomic analysis between Gleason-high or -low tumor and TAN samples among Blacks, among Whites, or between Blacks and Whites with Gleason-high or –low PCa. Among differential ARS/Ts identified between tumors and TANs among Blacks, 532 are unique to Gleason-high and 673 are unique to Gleason-low. Among differential ARS/Ts between Blacks and Whites, 360 are unique to Gleason-high and 242 are unique to Gleason-low. Interestingly, we found that even in TANs, there are 802 differential ARS/Ts between Blacks and Whites, with 459 and 343 in Gleason-high and Gleason-low, respectively. Among the genes undergoing differential ARS/Ts between Blacks and Whites are FGFR1, AKT1, H6PD, MDM2, and RAD51D in Gleason-high and CDK7 and VEGFA in Gleason-low. Notably, the number of genes undergoing ARS/Ts between Blacks and Whites with Gleason-high or -low tumors was higher than the number of genes undergoing differential aggregate gene expression between Blacks and Whites. Using gene set enrichment analysis, we found that genes undergoing ARS/Ts function in cancer relevant pathways. For example, the genes undergoing ARS/Ts between Blacks and Whites with Gleason-high or -low tumors were enriched in spermatogenesis and P53 hallmark pathways, respectively. Importantly, survival analysis shows a number of differential ARS/Ts between Blacks and Whites with Gleason-high or -low tumors are individually associated with progression-free survival. In summary, we have investigated the biology of PCa and TAN tissue between Black and White patients at the exon level. A number of genes undergoing newly identified differential ARS/Ts between Blacks and Whites are in genes reported to promote cancer aggressiveness and a number are in genes whose function in cancer was unreported prior to our findings, and a number are associated with patient progression-free survival. Our findings have identified novel targets with potential for precision oncology for PCa. Estimation of genetic ancestry of study participants and in vitro and in vivo validation of prioritized targets for PCa biology are underway. Citation Format: Muthana Al Abo, Wen-Chi Foo, Lauren Howard, Monika Anand, Daniel J. George, Steven R. Patierno, Jennifer A Freedman. Differential alternative RNA splicing and transcription events between Black and White prostate cancer patients involve genes promoting cancer aggressiveness and associate with patient survival [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A001.