ERG rearrangement in local recurrences compared to distant metastases of castration-resistant prostate cancer

Scheble, Veit; Scharf, Gregor; Braun, Martin; Ruiz, Christian; Stürm, Susanna; Petersen, Karl-Georg; Beschorner, Rudi; Bachmann, Alexander; Zellweger, Tobias; Fend, Falko; Kristiansen, Glen; Bubendorf, Lukas; Wernert, Nicolas; Shaikhibrahim, Zaki; Perner, Sven

doi:10.1007/s00428-012-1270-7

Cited by 12 publications

(13 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This finding is consistent with previous reports that the TMPRSS2-ERG fusion is frequently reported in primary PCa (40-50%) [2, 2, 4-11] but is slightly less common in PCa metastases (25-40%) [6, 8, 9, 12, 13]. This difference may indicate ERG is important in primary PCa, yet ERG expression may no longer be required in subgroups of CRPC metastases which may have acquired additional mutations/rearrangements, promoting proliferation and survival irrespective of ERG expression.…”

Section: Discussionsupporting

confidence: 93%

“…The most frequent fusion involves the ‘ETS-related gene’ or ‘ERG’ occurring in approximately 40-50% of primary prostate cancer (PCa) [2-11] with slightly less prevalence in PCa metastases (∼25-40%) [6, 8, 9, 12, 13]. Interestingly, there are a number of clinical studies suggesting worsened clinical prognosis with presence of this TMPRSS2-ERG gene fusion [4, 7, 14-17] as well as studies reporting the opposite [5, 18-22].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Characterizing the molecular features of ERG-positive tumors in primary and castration resistant prostate cancer

et al. 2016

View full text Add to dashboard Cite

Background The TMPRSS2-ERG gene fusion is detected in approximately half of primary prostate cancers (PCa) yet the prognostic significance remains unclear. We hypothesized that ERG promotes the expression of common genes in primary PCa and metastatic castration-resistant PCa (CRPC), with the objective of identifying ERG-associated pathways, which may promote the transition from primary PCa to CRPC. Methods We constructed tissue microarrays (TMA) from 127 radical prostatectomy specimens, 20 LuCaP patient-derived xenografts (PDX), and 152 CRPC metastases obtained immediately at time of death. Nuclear ERG was assessed by immunohistochemistry (IHC). To characterize the molecular features of ERG-expressing PCa, a subset of IHC confirmed ERG+ or ERG-specimens including 11 radical prostatectomies, 20 LuCaP PDXs, and 45 CRPC metastases underwent gene expression analysis. Genes were ranked based on expression in primary PCa and CRPC. Common genes of interest were targeted for IHC analysis and expression compared with biochemical recurrence (BCR) status. Results IHC revealed that 43% of primary PCa, 35% of the LuCaP PDXs, and 18% of the CRPC metastases were ERG+ (12 of 48 patients [25%] had at least 1 ERG+ metastasis). Based on gene expression data and previous literature, two proteins involved in calcium signaling (NCALD, CACNA1D), a protein involved in inflammation (HLA-DMB), CD3 positive immune cells, and a novel ERG-associated protein, DCLK1 were evaluated in primary PCa and CRPC metastases. In ERG+ primary PCa, a weak association was seen with NCALD and CACNA1D protein expression. HLA-DMB expression and the presence of CD3 positive immune cells were decreased in CRPC metastases compared to primary PCa. DCLK1 was upregulated at the protein level in unpaired ERG+ primary PCa and CRPC metastases (p=0.0013 and p<0.0001, respectively). In primary PCa, ERG status or expression of targeted proteins was not associated with BCR-free survival. However for primary PCa, ERG+DCLK1+ patients exhibited shorter time to BCR (p=0.06) compared with ERG+DCLK1- patients. Conclusions This study examined ERG expression in primary PCa and CRPC. We have identified altered levels of inflammatory mediators associated with ERG expression. We determined expression of DCLK1 correlates with ERG expression and may play a role in primary PCa progression to metastatic CPRC.

show abstract

Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Characterizing the molecular features of ERG-positive tumors in primary and castration resistant prostate cancer

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Abnormal expression of TFF3 was observed in various cancers, such as breast [19], ovarian [20], and thyroid cancers [21]. As shown by multivariate survival analysis in our research, TFF3 is an independent prognostic factor for gastric cancer, which is in agreement with previous studies [14][15][16].…”

Section: Discussionsupporting

confidence: 92%

Significance of TFF3 protein and Her-2/neu status in patients with gastric adenocarcinoma

Wei

et al. 2013

Pathology - Research and Practice

View full text Add to dashboard Cite

“…12,13 Very recently, we observed a higher frequency of ERG rearrangements (45%) in recurrent CR PC specimens and a lower frequency of 25% in metastatic CR PCs. 13 In contrast to the rearrangement, which is present on a genomic level, ERG protein expression is more dynamic, as it depends on the presence and activation of the androgen receptor (AR). In the CR disease state, the tumor may adapt to very low levels of androgens.…”

Section: Introductionmentioning

confidence: 76%

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

Gsponer

Braun²,

Scheble³

et al. 2014

Prostate Cancer Prostatic Dis

View full text Add to dashboard Cite

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.

show abstract

ERG rearrangement in local recurrences compared to distant metastases of castration-resistant prostate cancer

Cited by 12 publications

References 24 publications

Characterizing the molecular features of ERG-positive tumors in primary and castration resistant prostate cancer

Characterizing the molecular features of ERG-positive tumors in primary and castration resistant prostate cancer

Significance of TFF3 protein and Her-2/neu status in patients with gastric adenocarcinoma

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

Contact Info

Product

Resources

About