ERG rearrangement and protein expression in the progression to castration-resistant prostate cancer

Gsponer, Joël; Braun, Martin; Scheble, Veit; Zellweger, Tobias; Bachmann, Alexander; Perner, Sven; Vlajnic, Tatjana; Srivastava, Meera; Tan, Shyh‐Han; Dobi, Albert; Sesterhenn, Isabell A.; Srivastava, Shiv; Bubendorf, Lukas; Ruiz, Christian

doi:10.1038/pcan.2013.62

Cited by 16 publications

(17 citation statements)

References 33 publications

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“…Another consideration is that ERG protein expression is largely lost in the poorly differentiated T-Δ-Erg/Pten -null tumors (20), whereas the majority of human PCas with TMPRSS2-ERG fusions retain ERG overexpression (35–38). However, a small subset of human fusion-positive castration-resistant cases (e.g., small cell/neuroendocrine PCa) were also found to be negative for ERG protein staining (39). Whether our T-Δ-Erg/Pten -null model recapitulates this subset of human PCa requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Deletion of Interstitial Genes between TMPRSS2 and ERG Promotes Prostate Cancer Progression

et al. 2016

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TMPRSS2-ERG gene fusions that occur frequently in human prostate cancers can be generated either through insertional chromosomal rearrangement or by intrachromosomal deletion. Genetically, a key difference between these two mechanisms is that the latter results in deletion of a ~3Mb interstitial region containing genes with unexplored roles in prostate cancer. In this study, we characterized two mouse models recapitulating TMPRSS22-ERG insertion or deletion events in the background of prostate-specific PTEN deficiency. We found that only the mice which lacked interstitial region developed prostate adenocarcinomas marked by poor differentiation and epithelial-to-mesenchymal transition. Mechanistic investigations identified several interstitial genes, including Ets2 and Bace2, whose reduced expression correlated in the gene homologs in human prostate cancer with biochemical relapse and lethal disease. Accordingly, PTEN-deficient mice with prostate-specific knockout of Ets2 exhibited marked progression of prostate adenocarcinomas that was partly attributed to activation of MAPK signaling. Collectively, our findings established that Ets2 is a tumor suppressor gene in prostate cancer and its loss along with other genes within the TMPRSS2-ERG interstitial region contributes to disease progression.

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Section: Discussionmentioning

confidence: 99%

Deletion of Interstitial Genes between TMPRSS2 and ERG Promotes Prostate Cancer Progression

et al. 2016

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“…In a small percentage (6%) of prostate tumors, the ETS gene ELK4 is deregulated due to cis-splicing of the adjacent SLC45A3 gene and with no apparent chromosomal rearrangement [157,158]. Moreover, it has been shown that TMPRSS2-ETS rearrangements also occur in CRPC providing strong evidence that ERG fusions represent an aggressive molecular subtype of PC suggesting the existence of castration-resistant mechanisms of TMPRSS2 expression in prostate [159,160]. In CRPC, one function of TMPRSS2-ERG is proposed to be the expansion of self-renewing cells, which may serve as targets for subsequent mutations [161].…”

Section: Gene Fusionsmentioning

confidence: 97%

The hallmarks of castration-resistant prostate cancers

Katsogiannou

Ziouziou

Karaki

et al. 2015

Cancer Treatment Reviews

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“…Previously studies identified a subgroup PCa harboring TMPRSS2:ERG fusions but without detectable ERG protein expression in CRPC patients. 28 This subgroup showed significantly lower levels of androgen receptor (AR) protein expression and androgenregulated serum PSA and might represent a subset of patients with CRPC who may not benefit from conventional ADT. Another report found that TMPRSS2:ERG gene fusion can be detected by FISH in androgen-independent, AR-negative xenografts, and AR-negative clinical PCa specimens.…”

Section: The Heterogeneity Of Erg Expression Revealed the Biologicamentioning

confidence: 99%

The expression profile and heterogeneity analysis of ERG in 633 consecutive prostate cancers from a single center

et al. 2019

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Background: Overexpression of ERG protein resulting from TMPRSS2:ERG rearrangement is highly specific for prostate cancer (PCa). However, the biological function of this fusion protein and its relationship with clinicopathological features still remain controversial.Method: In this study, we evaluated ERG protein expression/gene rearrangement and heterogeneity by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in a cohort of 633 consecutive PCa initially diagnosed by core-needle biopsy in the West China Hospital.Result: Overall, ERG protein expression was detected in 16.7% (106 of 633) cases, and frequently observed in PCa patients less than 60 years of age (31.9% vs 15.5%, P = 0.004) and in PCa with Gleason score less than 8 (20.0% vs 13.4%, P = 0.027), but infrequently observed in cases with intraductal carcinoma of the prostate (IDC-P) (10.0% vs 18.6%, P = 0.012). Follow-up analysis found that patients who progressed to castration-resistant prostate cancer (CRPC) have a lower frequency of ERG protein expression at initial biopsies compared to androgen deprivation therapy (ADT)-sensitive cases (14.1% vs 23.5%, P = 0.042), but Kaplan-Meier curve showed that ERG protein expression was not an independent prognostic marker. Of all the 106 ERG-positive cases, eight cases (7.5%) exhibited heterogeneous expression of ERG protein, in which ERG was only positive in tumors with Gleason pattern 3, but negative in Gleason pattern 4. The FISH analysis was consistent with IHC in six of these cases. In the other two cases, ERG rearrangement was detected in tumors with both Gleason pattern 3 and 4 by FISH, despite the negative protein expression in Gleason pattern 4. In case 1, a repeated biopsy was performed when the disease progressed to CRPC, and no ERG-positive cells were identified neither by IHC nor FISH. Conclusion:This was by far the largest series of ERG expression and heterogeneity analysis in Chinese PCa. The ERG rearrangement seemed to be frequently expressed in patients with relatively younger age and lower Gleason score and infrequently expressed in PCa with the IDC-P. PCa with positive ERG were less frequently to progress to CRPC, but there was no prognostic significance of ERG expression. In heterogeneous cases, ERG protein was detectable only in tumors with Gleason

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ERG rearrangement and protein expression in the progression to castration-resistant prostate cancer

Cited by 16 publications

References 33 publications

Deletion of Interstitial Genes between TMPRSS2 and ERG Promotes Prostate Cancer Progression

Deletion of Interstitial Genes between TMPRSS2 and ERG Promotes Prostate Cancer Progression

The hallmarks of castration-resistant prostate cancers

The expression profile and heterogeneity analysis of ERG in 633 consecutive prostate cancers from a single center

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