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. (Cancer Res 2006; 66(21): 10242-6)

Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer

“…When this fusion has occurred, the 3 0 -centromeric and 5 0 -telomeric ends of ERG occur as separated red and green signals (Figure 1b; Tomlins et al, 2005;Perner et al, 2006). Many cancers with alteration in the ERG gene FISH pattern also exhibit loss of the lone green 5 0 -ERG signal (Figures 1c-e), consistent with previous findings that the chromosomal region between TMPRSS2 and ERG on chromosome 21 is frequently deleted in cancers with TMPRSS-ERG fusions (Iljin et al, 2006;Perner et al, 2006).…”

“…The failure to observe worse clinical outcome in class Esplit cancers indicates that the loss of sequences 5 0 to ERG found in Edel cancers is also critical to cancer aggression. It has been shown by several groups (Hermans et al, 2006;Iljin et al, 2006;Perner et al, 2006) that fusion of the tandemly arranged TMPRSS2 and ERG fusions in prostate cancer is frequently accompanied by loss of the entire intervening chromosome 21 sequence, so a search of this region for genes with a tumour-suppressive effect may be a fruitful avenue of future investigation. Wang et al (2006) have provided evidence that the presence of a particular fusion transcript between exon 2 of TMPRSS2 and exon 4 of ERG that encodes a TMPRSS2-ERG fusion protein may also be associated with aggressive disease.…”

“…Although a useful prognostic indicator, as a system based on morphological appearance, it suffers from problems of interobserver variability (Allsbrook et al, 2001a, b;Oyama et al, 2005;Melia et al, 2006;van der Kwast et al, 2006) and of changes in interpretation with time (Smith et al, 2002;Chism et al, 2003;Albertsen et al, 2005). Recently, fusion of the TMPRSS2 gene to the ETS transcription factor gene ERG has been reported as a common event in prostate cancer (Tomlins et al, 2005Hermans et al, 2006;Iljin et al, 2006;Perner et al, 2006;Soller et al, 2006;Wang et al, 2006;Yoshimoto et al, 2006;Clark et al, 2007). Less frequently TMPRSS2 also becomes fused to ETV1 and ETV4 (Tomlins et al, 2005Hermans et al, 2006).…”

Gene fusions between TMPRSS2 and ETS family genes in prostate cancer: frequency and transcript variant analysis by RT-PCR and FISH on paraffin-embedded tissues

“…It is currently unclear whether this microdeletion of chromosome 21q would carry additional biological significance beyond the ERG activation, a view that was recently entertained. 16,17 The finding that TMPRSS2-ETS fusion is seen in approximately half of the prostate cancer also raises the issue of whether the fusion-positive and fusion-negative cases would differ biologically, for instance, in their histomorphology, response to treatment or prognosis. Previous studies have shown no correlation to Gleason's grades, lymph node status or clinical stages, 16 and Demichelis et al 21 suggested that TMPRSS2-ERG fusion-positive carcinomas might represent a more aggressive phenotype.…”

“…15 Thus, the TMPRSS2-ERG fusion could result either from balanced or unbalanced translocation, or from deletion of the intervening DNA segment, and the literature to date suggests deletion as the more frequent event. 16,17 In the present study, we evaluated a series of 82 formalin-fixed paraffin-embedded prostate cancer specimens, by RT-PCR and by FISH analyses. TMPRSS2-ERG fusion was observed in 43% of the cases, more commonly resulting from deletion than translocation.…”