title: TMPRSS2 fusions with oncogenic ETS factors in prostate cancer involve unbalanced genomic rearrangements and are associated with HDAC1 and epigenetic reprogramming.
abstract: Translocations fusing the strong androgen-responsive gene, TMPRSS2, with ERG or other oncogenic ETS factors may facilitate prostate cancer development. Here, we studied 18 advanced prostate cancers for ETS factor alterations, using reverse transcription-PCR and DNA and RNA array technologies, and identified putative ERG downstream gene targets from the microarray data of 410 prostate samples. Out of the 27 ETS factors, ERG was most frequently overexpressed. Seven cases showed TMPRSS2:ERG gene fusions, whereas the TMPRSS2:ETV4 fusion was seen in one case. In five out of six tumors with high ERG expression, array-CGH analysis revealed interstitial 2.8 Mb deletions between the TMPRSS2 and ERG loci, or smaller, unbalanced rearrangements. In silico analysis of the ERG gene coexpression patterns revealed an association with high expression of the histone deacetylase 1 gene, and low expression of its target genes. Furthermore, we observed increased expression of WNT-associated pathways and down-regulation of tumor necrosis factor and cell death pathways. In summary, our data indicate that the TMPRSS2:ERG translocation is common in advanced prostate cancer and occurs by virtue of unbalanced genomic rearrangements. Activation of ERG by fusion with TMPRSS2 may lead to epigenetic reprogramming, WNT signaling, and down-regulation of cell death pathways, implicating ERG in several hallmarks of cancer with potential therapeutic importance.
authors.affiliation: Medical Biotechnology, VTT Technical Research Centre of Finland and University of Turku, Turku, Finland.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Iljin
authors.forename: Maija
authors.initials: M
authors.lastname: Wolf
authors.forename: Henrik
authors.initials: H
authors.lastname: Edgren
authors.forename: Santosh
authors.initials: S
authors.lastname: Gupta
authors.forename: Sami
authors.initials: S
authors.lastname: Kilpinen
authors.forename: Rolf I
authors.initials: RI
authors.lastname: Skotheim
authors.forename: Mari
authors.initials: M
authors.lastname: Peltola
authors.forename: Frank
authors.initials: F
authors.lastname: Smit
authors.forename: Gerald
authors.initials: G
authors.lastname: Verhaegh
authors.forename: Jack
authors.initials: J
authors.lastname: Schalken
authors.forename: Matthias
authors.initials: M
authors.lastname: Nees
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
mesh_terms: D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics; D044127:Epigenesis, Genetic; D050939:Gene Fusion; D015321:Gene Rearrangement; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008297:Male; D009693:Nucleic Acid Hybridization; D011471:Prostatic Neoplasms / Q000235:genetics*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics*; D012697:Serine Endopeptidases / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics; D000071230:Transcriptional Regulator ERG
chemical_list: D004268:DNA-Binding Proteins; C072312:ERG protein, human; D050783:Proto-Oncogene Proteins c-ets; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases