Abstract
BackgroundTMPRSS2-ERG gene fusions occur in about 50% of all prostate cancer cases and represent promising markers for molecular subtyping. Although TMPRSS2-ERG fusion seems to be a critical event in prostate cancer, the precise functional role in cancer development and progression is still unclear.MethodsWe studied large-scale gene expression profiles in 47 prostate tumor tissue samples and in 48 normal prostate tissue samples taken from the non-suspect area of clinical low-risk tumors using Affymetrix GeneChip Exon 1.0 ST microarrays.ResultsComparison of gene expression levels among TMPRSS2-ERG fusion-positive and negative tumors as well as benign samples demonstrated a distinct transcriptional program induced by the gene fusion event. Well-known biomarkers for prostate cancer detection like CRISP3 were found to be associated with the gene fusion status. WNT and TGF-β/BMP signaling pathways were significantly associated with genes upregulated in TMPRSS2-ERG fusion-positive tumors.ConclusionsThe TMPRSS2-ERG gene fusion results in the modulation of transcriptional patterns and cellular pathways with potential consequences for prostate cancer progression. Well-known biomarkers for prostate cancer detection were found to be associated with the gene fusion. Our results suggest that the fusion status should be considered in retrospective and future studies to assess biomarkers for prostate cancer detection, progression and targeted therapy.
Highlights
TMPRSS2-ERG gene fusions occur in about 50% of all prostate cancer cases and represent promising markers for molecular subtyping
TMPRSS2-ERG induced transcriptional deregulation Gene expression profiles were successfully obtained from cancer and normal prostate tissues taken from nonsuspect areas of the peripheral zone from clinical low-risk tumors
Our gene expression data indicate a deregulation of WNT and TGF-b/BMP signaling in fusion-positive prostate tumors
Summary
TMPRSS2-ERG gene fusions occur in about 50% of all prostate cancer cases and represent promising markers for molecular subtyping. Since the discovery of a recurrent gene fusion between the androgen responsive gene TMPRSS2 (transmembrane protease, serine 2) and ERG (v-ets erythroblastosis virus E26 homolog (avian)) on chromosome 21 [2], prostate cancers are molecularly divided into “fusion-positive” and “fusion-negative” cancers. Initial in vitro experiments demonstrated that ERG overexpression leads to increased invasion via the induction of metalloproteinase and plasminogen activator pathway genes [11]. The molecular effects of the gene fusion were recently found to be associated with an activation of WNT-signaling which induces epithelial-tomesenchymal transition (EMT) and loss of cell adhesion [12,13]. ERG overexpression was shown to modulate androgen receptor signaling and to initiate epigenetic silencing resulting in cellular dedifferentiation [14]
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