TMPRSS2:ERG fusion by translocation or interstitial deletion is highly relevant in androgen-dependent prostate cancer, but is bypassed in late-stage androgen receptor-negative prostate cancer.
Recently, a unique fusion between the prostate-specific, androgen-regulated TMPRSS2 gene and the ETS genes ERG, ETV1, or ETV4 has been described in clinical prostate cancer. We investigated mechanisms of expression of four ETS genes, ERG, ETV1, ETV4, and FLI1, in 11 xenografts representing different stages of prostate cancer. All five androgen-dependent xenografts showed as major transcript overexpression of two splice variants of TMPRSS2:ERG, linking TMPRSS2 exon 1 or 2 sequences to ERG exon 4. In one of two androgen-sensitive xenografts, fusion transcripts of TMPRSS2 and ETV1 were detected. Array-based comparative genomic hybridization and interphase fluorescence in situ hybridization indicated both interstitial deletions and translocations as mechanisms of TMPRSS2:ERG gene fusion. Importantly, TMPRSS2 to ERG fusions were also observed in three of four androgen-independent, androgen receptor (AR)-negative xenografts and in two AR-negative clinical prostate cancer specimens; however, the fusion gene was not expressed. In almost all AR-negative tumor samples, overexpression of wild-type ETV4 or FLI1 was detected. Combined, our observations indicate a key role of fusion of TMPRSS2 and ETS genes in most androgen-regulated prostate cancers, which might be bypassed by androgen-independent expression of wild-type ETS factors in late-stage disease.
Hermans
Karin G
KG
Departments of Pathology and Urology, Josephine Nefkens Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
van Marion
Ronald
R
van Dekken
Herman
H
Jenster
Guido
G
van Weerden
Wytske M
WM
Trapman
Jan
J
D000818:Animals; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D015536:Down-Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009367:Neoplasm Staging; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000172:deficiency; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000235:genetics*; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*; D000071230:Transcriptional Regulator ERG; D014178:Translocation, Genetic; D014183:Transplantation, Heterologous
D004268:DNA-Binding Proteins; C072312:ERG protein, human; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D011944:Receptors, Androgen; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human