ERG rearrangement and protein expression in the progression to castration-resistant prostate cancer.
BACKGROUND
Approximately half of the prostate carcinomas are characterized by a chromosomal rearrangement fusing the androgen-regulated gene TMPRSS2 to the oncogenic ETS transcription factor ERG. Aim of this study was to comprehensively analyze the role and impact of the ERG rearrangement and protein expression on the progression to castration-resistant (CR) disease.


METHODS
We used a tissue microarray (TMA) constructed from 114 hormone naive (HN) and 117 CR PCs. We analyzed the ERG rearrangement status by fluorescence in situ hybridization and the expression profiles of ERG, androgen receptor (AR) and the proliferation marker Ki67 by immunohistochemistry.


RESULTS
Nearly half of the PC tissue specimens (HN: 38%, CR: 46%) harbored a TMPRSS2-ERG gene fusion. HN PCs with positive translocation status showed increased tumor cell proliferation (P<0.05). As expected, TMPRSS2-ERG gene fusion was strongly associated with increased ERG protein expression in HN and CR PCs (both P<0.0001). Remarkably, the study revealed a subgroup (26%) of CR PCs with ERG rearrangement but without any detectable ERG protein expression. This subgroup showed significantly lower levels of AR protein expression and androgen-regulated serum PSA (both P<0.05).


CONCLUSIONS
In this study, we identified a subgroup of ERG-rearranged CR PCs without detectable ERG protein expression. Our results suggest that this subgroup could represent CR PCs with a dispensed AR pathway. These tumors might represent a thus far unrecognized subset of patients with AR-independent CR PC who may not benefit from conventional therapy directed against the AR pathway.
Institute for Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.
J R
JR
Gsponer
Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Bonn, Germany.
M
M
Braun
Institute of Pathology, Comprehensive Cancer Center, University Hospital Tuebingen, Tuebingen, Germany.
V J
VJ
Scheble
Division of Urology, St Claraspital, Basel, Switzerland.
T
T
Zellweger
Department of Urology, University Hospital Basel, University of Basel, Basel, Switzerland.
A
A
Bachmann
Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Bonn, Germany.
S
S
Perner
Institute for Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.
T
T
Vlajnic
Department of Anatomy, Physiology, and Genetics, and Institute for Molecular Medicine, Uniformed Services University of the Health Sciences, School of Medicine, Bethesda, MD, USA.
M
M
Srivastava
Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
S H
SH
Tan
Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
A
A
Dobi
Joint Pathology Center, Silver Spring, MD, USA.
I A
IA
Sesterhenn
Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
S
S
Srivastava
Institute for Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.
L
L
Bubendorf
Institute for Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.
C
C
Ruiz
D018450:Disease Progression; D015321:Gene Rearrangement; D006801:Humans; D019394:Ki-67 Antigen / Q000235:genetics; D008297:Male; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000473:pathology; D011944:Receptors, Androgen; D012697:Serine Endopeptidases / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics*; D000071230:Transcriptional Regulator ERG; D059467:Transcriptome; D014178:Translocation, Genetic
C410798:AR protein, human; C072312:ERG protein, human; D019394:Ki-67 Antigen; D015514:Oncogene Proteins, Fusion; D011944:Receptors, Androgen; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human