Transcriptomes of Prostate Cancer with TMPRSS2:ERG and Other ETS Fusions

The most common somatic event in primary prostate cancer is a fusion between the androgen-related TMPRSS2 gene and the ERG oncogene. Tumors with these fusions, which occur early in carci-nogenesis, have a distinctive etiology. A smaller subset of other tumors harbor fusions between TMPRSS2 and members of the ETS transcription factor family other than ERG. To assess the genomic similarity of tumors with non -ERG ETS fusions and those with fusions involving ERG, this study derived a transcriptomic signature of non -ERG ETS fusions and assessed this signature and ERG -related gene expression in 1,050 men with primary prostate cancer from three independent population-based and hospital-based stud-ies. Although non -ERG ETS fusions involving ETVT, ETV4, ETV5, or FLIT were individually rare, they jointly accounted for one in seven prostate tumors. Genes differentially regulated between non -ERG ETS tumors and tumors without ETS fusions showed similar differential expression when ERG tumors and tumors without ETS fusions were compared (differences explained: R2 = 69-77%), including ETS-related androgen receptor (AR) target genes. Differ-ences appeared to result from similarities among ETS tumors rather than similarities among non-ETS tumors. Gene sets associated with ERG fusions were consistent with gene sets associated with non -ERG ETS fusions, including fatty acid and amino acid metabolism, an observation that was robust across cohorts.Implications: Considering ETS fusions jointly may be useful for etiologic studies on prostate cancer, given that the transcriptome is profoundly impacted by ERG and non -ERG ETS fusions in a largely similar fashion, most notably genes regulating metabolic pathways.