Abstract 1219: Unraveling alternative polyadenylation in prostate cancer with CORE-PAD

Abstract

Abstract Mechanisms that control gene expression at the RNA level are often referred to as post-transcriptional regulation (PTR) mechanisms. Splicing and polyadenylation (PA) are well-known examples of PTR that can regulate not only gene expression but also their function. Alternative Polyadenylation (APA) has already been shown to be essential to many biological processes (e.g., proliferation, cell differentiation, etc) and has also been implicated in the development and progression of multiple diseases (e.g., cancer, hematological and immune disorders, etc.). Although several sequencing methods have been developed to sequence only the transcript termination site (TTS), the number of publicly available data derived from these methods is extremely limited in comparison to traditional RNA-Seq data. To overcome this limitation, we created a new framework - Compositional Regression of Polyadenylation Differences (CORE-PAD) - for the study of differential APA events using traditional bulk RNA-seq data. Through simulated data, we showed that CORE-PAD has higher accuracy than other methods (accuracy = 0.98) in detecting APA events. We applied CORE-PAD across prostate cancer (PCa) samples with impaired CDK12 and “wild” samples. We found multiple genes presented differential PA site usage, including DNA repair genes. Most notably, we notice that many genes that exhibit differential APA were not differentially expressed at gene level, meaning they are potentially “silent drivers” that cannot be capture through standard differential gene expression analysis. These findings highlight the importance of studying APA, which can help shed light into another layer of regulation occurring between transcription and translation. This is especially important since these events can be source of neoantigens or targeted mRNA degradation which could be explore for new treatments. Finally, the CORE-PAD framework was designed to take advantage of our recently published recount3 resource making over 750,000 RNA-Seq samples of human and mouse origin readily available for analysis, enabling studies of APA across thousands of phenotypes in an accurate and accessible way. Citation Format: Eddie L. Imada, Christopher Wilks, Ben Langmead, Luigi Marchionni. Unraveling alternative polyadenylation in prostate cancer with CORE-PAD [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 1219.