Distinct transcriptional repertoire of the androgen receptor in ETS fusion-negative prostate cancer

Background: Prostate cancer (PCa) tumors harboring translocations of ETS family genes with the androgen responsive TMPRSS2 gene (ETS+ tumors) provide a robust biomarker for detecting PCa in approximately 70% of patients. ETS+ PCa express high levels of the androgen receptor (AR), yet PCa tumors lacking ETS fusions (ETS−) also express AR and demonstrate androgen-regulated growth. In this study, we evaluate the differences in the AR-regulated transcriptomes between ETS+ and ETS− PCa tumors. Methods: 10,608 patient tumors from three independent PCa datasets classified as ETS+ (samples overexpressing ERG or other ETS family members) or ETS− (all other PCa) were analyzed for differential gene expression using false-discovery-rate adjusted methods and gene-set enrichment analysis (GSEA). Results: Based on the expression of AR-dependent genes and an unsupervised Principal Component Analysis (PCA) model, AR-regulated gene expression alone was able to separate PCa samples into groups based on ETS status in all PCa databases. ETS status distinguished several differentially expressed genes in both TCGA (6.9%) and GRID (6.6%) databases, with 413 genes overlapping in both databases. Importantly, GSEA showed enrichment of distinct androgen-responsive genes in both ETS− and ETS+ tumors, and AR ChIP-seq data identified 131 direct AR-target genes that are regulated in an ETS-specific fashion. Notably, dysregulation of ETS-dependent AR-target genes within the metabolic and non-canonical WNT pathways was associated with clinical outcomes. Conclusions: ETS status influences the transcriptional repertoire of the AR, and ETS− PCa tumors appear to rely on distinctly different AR-dependent transcriptional programs to drive and sustain tumorigenesis.