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 carcinogenesis, 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 studies. While non-ERG ETS fusions involving ETV1, ETV4, ETV5, or FLI1 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. Differences 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.
Molecular cancer research : MCR. 2022 Sep 20 [Epub ahead of print]
Konrad H Stopsack, Xiaofeng A Su, J Bailey Vaselkiv, Rebecca E Graff, Ericka M Ebot, Andreas Pettersson, Rosina T Lis, Michelangelo Fiorentino, Massimo Loda, Kathryn L Penney, Tamara L Lotan, Lorelei A Mucci
Harvard T.H. Chan School of Public Health, Boston, MA, United States., Massachusetts Institute of Technology, Cambridge, MA, United States., University of California, San Francisco, San Francisco, CA, United States., Dana-Farber Cancer Institute, Boston, MA, United States., University of Bologna, Bologna, Italy., Weill Cornell Medicine, New York, NY, United States., Brigham and Women's Hospital/Harvard Medical School, Boston, MA, United States., Johns Hopkins University School of Medicine, Baltimore, MD, United States.