The landscape of alternative splicing in aggressive prostate cancers

We sought to define the landscape of alternative pre-mRNA splicing in prostate cancers and the relationship of exon choice to known genetic driver alterations. To do so, we compiled a meta-dataset comprised of RNA-Seq samples from publicly available sources representing a range of phenotypes from normal tissue to drug resistant metastases. We subjected these samples to exon-level analysis with purpose-built software. We then correlated transcriptional signatures of cancer driver pathways with these alternative splicing events and discovered that Myc signaling was correlated with incorporation of a set of cassette exons found in RNA binding proteins. We experimentally verified this finding in a human prostate cell transformation assay. Our results connect changes in alternative pre-mRNA splicing to oncogenic alterations common in prostate and many other cancers. We also establish a role for Myc in regulating RNA processing by controlling the incorporation of nonsense mediated decay-determinant exons in RNA binding proteins. Overall design: Whole transcriptome sequencing of three independent cell lines derived from the prostate epithelium of three different human specimens. c-Myc was withdrawn over a time course and mRNA was collected at 0 and 24 hours. Also includes processed data files that represent RNA expression values and exon inclusion data (percent spliced in, PSI) for a prostate meta-dataset that includes de-identified normal prostate tissue and cancer samples combined from previously-published studies and presented here as part of a unified analysis.