ERG rearrangement and protein expression in the progression to castration-resistant prostate cancer
J R Gsponer1, M Braun2, V J Scheble3
1Institute for Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.
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.
Insights
Approximately half of prostate cancers have a TMPRSS2-ERG gene fusion. A subset of castration-resistant prostate cancers with this fusion lack ERG protein, suggesting an androgen receptor-independent pathway.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Prostate carcinomas often feature TMPRSS2-ERG gene fusions, impacting androgen-regulated pathways.
- Understanding ERG rearrangement and protein expression is crucial for analyzing castration-resistant prostate cancer (CRPC) progression.
Purpose of the Study:
- To comprehensively analyze the role and impact of ERG rearrangement and protein expression in CRPC progression.
- To investigate the association between ERG status and androgen receptor (AR) pathway activity in CRPC.
Main Methods:
- Utilized a tissue microarray (TMA) of hormone-naive (HN) and CR prostate cancer (PC) specimens.
- Analyzed ERG rearrangement via fluorescence in situ hybridization (FISH).
- Assessed ERG, AR, and Ki67 expression using immunohistochemistry (IHC).
Main Results:
- TMPRSS2-ERG gene fusion was present in 38% of HN and 46% of CR PCs.
- ERG rearrangement correlated with increased proliferation in HN PCs and ERG protein expression in both HN and CR PCs.
- A subgroup of CR PCs (26%) with ERG rearrangement showed no detectable ERG protein, alongside lower AR expression and PSA levels.
Conclusions:
- Identified a subgroup of ERG-rearranged CR PCs lacking ERG protein expression.
- This subgroup may represent CR PCs with a non-functional AR pathway.
- These findings suggest a potential subset of AR-independent CR PC patients who may not respond to conventional AR-targeted therapies.
