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Sven Perner - One of the best experts on this subject based on the ideXlab platform.
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prevalence of tmprss2 ERG and slc45a3 ERG Gene fusions in a large prostatectomy cohort
Modern Pathology, 2010Co-Authors: Raquel Esgueva, Veit Scheble, Florian R Fritzsche, Carsten Stephan, Manfred Dietel, Glen Kristiansen, Christopher J Lafargue, Michael Lein, Sven Perner, Mark A RubinAbstract:The majority of prostate cancers harbor recurrent Gene fusions between the hormone-regulated TMPRSS2 and members of the ETS family of transcription factors, most commonly ERG. Prostate cancer with ERG rearrangements represent a distinct sub-class of tumor based on studies reporting associations with histomorphologic features, characteristic somatic copy number alterations, and Gene expression signatures. This study describes the frequency of ERG rearrangement prostate cancer and three 5 prime (5′) Gene fusion partners (ie, TMPRSS2, SLC45A3, and NDRG1) in a large prostatectomy cohort. ERG Gene rearrangements and mechanism of rearrangement, as well as rearrangements of TMPRSS2, SLC45A3, and NDRG1, were assessed using fluorescence in situ hybridization (FISH) on prostate cancer samples from 614 patients treated using radical prostatectomy. ERG rearrangement occurred in 53% of the 540 assessable cases. TMPRSS2 and SLC45A3 were the only 5′ partner in 78% and 6% of these ERG rearranged cases, respectively. Interestingly, 11% of the ERG rearranged cases showed concurrent TMPRSS2 and SLC45A3 rearrangements. TMPRSS2 or SLC45A3 rearrangements could not be identified for 5% of the ERG rearranged cases. From these remaining cases we identified one case with NDRG1 rearrangement. We did not observe any associations with pathologic parameters or clinical outcome. This is the first study to describe the frequency of SLC45A3–ERG fusions in a large clinical cohort. Most studies have assumed that all ERG rearranged prostate cancers harbor TMPRSS2–ERG fusions. This is also the first study to report concurrent TMPRSS2 and SLC45A3 rearrangements in the same tumor focus, suggesting additional complexity that had not been previously appreciated. This study has important clinical implications for the development of diagnostic assays to detect ETS rearranged prostate cancer. Incorporation of these less common ERG rearranged prostate cancer fusion assays could further increase the sensitivity of the current PCR-based approaches.
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detection of tmprss2 ERG fusion Gene expression in prostate cancer specimens by a novel assay using branched dna
Urology, 2009Co-Authors: Botoul Maqsodi, Mark A Rubin, Sven Perner, Steven P Balk, Wen Yang, Gary Mcmaster, Meredith M Regan, Glenn J Bubley, Martin G SandaAbstract:OBJECTIVES To develop a novel assay that uses branched DNA technology to measure TMPRSS2-ERG fusion, as Genetic rearrangement of TMPRSS2 regulatory sequences and coding sequences of the ERG Gene has been detected in nearly half of prostate cancers, but quantitative assays to detect such TMPRSS2-ERG Gene fusion have been limited to real-time polymerase chain reaction (PCR) techniques that rely on reverse transcriptase-based amplification. METHODS Branched DNA probes were designed to detect TMPRSS2-ERG Gene fusion in prostate cancer cell lines. Nonquantitative nested reverse transcription (RT)-PCR and fluorescence in situ hybridization (FISH) were used to ascertain TMPRSS2-ERG Gene fusion status in prostate tissues. RESULTS The branched DNA assay detected TMPRSS2-ERG Gene fusion from less than 200 pg of prostate cancer RNA, whereas more than 600 pg of RNA was required for fusion Gene detection by one step real-time RT-PCR. In evaluation of clinical prostatectomy specimens, the branched DNA assay showed a concordant detectable fusion signal in all 9 clinical samples that had fusion detected by nested RT-PCR or FISH. Moreover, branched DNA detected Gene fusion in 2 of 16 prostate cancer tissue specimens that was not detected by FISH or nested RT-PCR. CONCLUSIONS Our findings demonstrate a branched DNA assay that is effective for detection of TMPRSS2-ERG Gene fusion in prostate cancer clinical specimens, thus providing an alternative method to ascertain TMPRSS2-ERG Gene fusion in human prostate cancer tissue.
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prevalence of tmprss2 ERG fusion prostate cancer among men undERGoing prostate biopsy in the united states
Clinical Cancer Research, 2009Co-Authors: Juan Miguel Mosquera, Rajal B Shah, Sven Perner, Elizabeth M Genega, Rohit Mehra, Meredith M Regan, Gerri Bueti, Sandra M Gaston, Scott A TomlinsAbstract:Purpose: Fusion of the TMPRSS2 prostate-specific Gene with the ERG transcription factor is a putatively oncogenic Gene rearrangement that is commonly found in prostate cancer tissue from men undERGoing prostatectomy. However, the prevalence of the fusion was less common in samples of transurethral resection of the prostate from a Swedish cohort of patients with incidental prostate cancer followed by watchful waiting, raising the question as to whether the high prevalence in prostatectomy specimens reflects selection bias. We sought to determine the prevalence of TMPRSS2-ERG Gene fusion among prostate-specific antigen–screened men undERGoing prostate biopsy in the United States. Experimental Design: We studied 140 prostate biopsies from the same number of patients for TMPRSS2-ERG fusion status with a fluorescent in situ hybridization assay. One hundred and thirty-four samples (100 cancer and 34 benign) were assessable. Results: ERG Gene rearrangement was detected in 46% of prostate biopsies that were found to have prostate cancer and in 0% of benign prostate biopsies ( P TMPRSS2-ERG fusion–positive prostate cancer biopsies than Gene fusion–negative prostate cancer biopsies ( P ≤ 0.04). No significant association with Gleason score was detected. In addition, non-Caucasian patients were less likely to have positive fusion status ( P = 0.02). Conclusions: This is the first prospective North American multicenter study to characterize TMPRSS2-ERG prostate cancer prevalence in a cohort of patients undERGoing needle biopsy irrespective of whether or not they subsequently undERGo prostatectomy. Our results show that this Gene rearrangement is common among North American men who have prostate cancer on biopsy, is absent in benign prostate biopsy, and is associated with specific morphologic features. These findings indicate a need for prospective studies to evaluate the relationship of TMPRSS2-ERG rearrangement with clinical course of screening-detected prostate cancer in North American men, and a need for the development of noninvasive screening tests to detect TMPRSS2-ERG rearrangement.
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characterization of tmprss2 ERG fusion high grade prostatic intraepithelial neoplasia and potential clinical implications
Clinical Cancer Research, 2008Co-Authors: Sven Perner, Juan Miguel Mosquera, Martin G Sanda, Elizabeth M Genega, Matthias D HoferAbstract:Purpose: More than 1,300,000 prostate needle biopsies are done annually in the United States with up to 16% incidence of isolated high-grade prostatic intraepithelial neoplasia (HGPIN). HGPIN has low predictive value for identifying prostate cancer on subsequent needle biopsies in prostate-specific antigen–screened populations. In contemporary series, prostate cancer is detected in ∼20% of repeat biopsies following a diagnosis of HGPIN. Further, discrete histologic subtypes of HGPIN with clinical implication in management have not been characterized. The TMPRSS2-ERG Gene fusion that has recently been described in prostate cancer has also been shown to occur in a subset of HGPIN. This may have significant clinical implications given that TMPRSS2-ERG fusion prostate cancer is associated with a more aggressive clinical course. Experimental Design: In this study, we assessed a series of HGPIN lesions and paired prostate cancer for the presence of TMPRSS2-ERG Gene fusion. Results: Fusion-positive HGPIN was observed in 16% of the 143 number of lesions, and in all instances, the matching cancer shared the same fusion pattern. Sixty percent of TMPRSS2-ERG fusion prostate cancer had fusion-negative HGPIN. Conclusions: Given the more aggressive nature of TMPRSS2-ERG prostate cancer, the findings of this study raise the possibility that Gene fusion-positive HGPIN lesions are harbingers of more aggressive disease. To date, pathologic, molecular, and clinical variables do not help stratify which men with HGPIN are at increased risk for a cancer diagnosis. Our results suggest that the detection of isolated TMPRSS2-ERG fusion HGPIN would improve the positive predictive value of finding TMPRSS2-ERG fusion prostate cancer in subsequent biopsies.
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tmprss2 ERG Gene fusion associated with lethal prostate cancer in a watchful waiting cohort
Oncogene, 2007Co-Authors: Sven Perner, Francesca Demichelis, F Schmidt, Sunita R Setlur, Katja Fall, Ove AndrenAbstract:The identification of the TMPRSS2:ERG fusion in prostate cancer suggests that distinct molecular subtypes may define risk for disease progression. In surgical series, TMPRSS2:ERG fusion was identified in 50% of the tumors. Here, we report on a population-based cohort of men with localized prostate cancers followed by expectant (watchful waiting) therapy with 15% (17/111) TMPRSS2:ERG fusion. We identified a statistically significant association between TMPRSS2:ERG fusion and prostate cancer specific death (cumulative incidence ratio=2.7, P<0.01, 95% confidence interval=1.3–5.8). Quantitative reverse-transcription–polymerase chain reaction demonstrated high estrogen-regulated Gene (ERG) expression to be associated with TMPRSS2:ERG fusion (P<0.005). These data suggest that TMPRSS2:ERG fusion prostate cancers may have a more aggressive phenotype, possibly mediated through increased ERG expression.
Steven P Balk - One of the best experts on this subject based on the ideXlab platform.
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detection of tmprss2 ERG fusion Gene expression in prostate cancer specimens by a novel assay using branched dna
Urology, 2009Co-Authors: Botoul Maqsodi, Mark A Rubin, Sven Perner, Steven P Balk, Wen Yang, Gary Mcmaster, Meredith M Regan, Glenn J Bubley, Martin G SandaAbstract:OBJECTIVES To develop a novel assay that uses branched DNA technology to measure TMPRSS2-ERG fusion, as Genetic rearrangement of TMPRSS2 regulatory sequences and coding sequences of the ERG Gene has been detected in nearly half of prostate cancers, but quantitative assays to detect such TMPRSS2-ERG Gene fusion have been limited to real-time polymerase chain reaction (PCR) techniques that rely on reverse transcriptase-based amplification. METHODS Branched DNA probes were designed to detect TMPRSS2-ERG Gene fusion in prostate cancer cell lines. Nonquantitative nested reverse transcription (RT)-PCR and fluorescence in situ hybridization (FISH) were used to ascertain TMPRSS2-ERG Gene fusion status in prostate tissues. RESULTS The branched DNA assay detected TMPRSS2-ERG Gene fusion from less than 200 pg of prostate cancer RNA, whereas more than 600 pg of RNA was required for fusion Gene detection by one step real-time RT-PCR. In evaluation of clinical prostatectomy specimens, the branched DNA assay showed a concordant detectable fusion signal in all 9 clinical samples that had fusion detected by nested RT-PCR or FISH. Moreover, branched DNA detected Gene fusion in 2 of 16 prostate cancer tissue specimens that was not detected by FISH or nested RT-PCR. CONCLUSIONS Our findings demonstrate a branched DNA assay that is effective for detection of TMPRSS2-ERG Gene fusion in prostate cancer clinical specimens, thus providing an alternative method to ascertain TMPRSS2-ERG Gene fusion in human prostate cancer tissue.
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reactivation of androgen receptor regulated tmprss2 ERG Gene expression in castration resistant prostate cancer
Cancer Research, 2009Co-Authors: Changmeng Cai, Hongyun Wang, Shaoyong Chen, Steven P BalkAbstract:It seems clear that androgen receptor (AR)-regulated expression of the TMPRSS2:ERG fusion Gene plays an early role in prostate cancer (PC) development or progression, but the extent to which TMPRSS2:ERG is down-regulated in response to androgen deprivation therapy (ADT) and whether AR reactivates TMPRSS2:ERG expression in castration-resistant PC (CRPC) have not been determined. We show that ERG message levels in TMPRSS2:ERG fusion-positive CRPC are comparable with the levels in fusion Gene-positive primary PC, consistent with the conclusion that the TMPRSS2:ERG expression is reactivated by AR in CRPC. To further assess whether TMPRSS2:ERG expression is initially down-regulated in response to ADT, we examined VCaP cells, which express the TMPRSS2:ERG fusion Gene, and xenografts. ERG message and protein rapidly declined in response to removal of androgen in vitro and castration in vivo. Moreover, as observed in the clinical samples, ERG expression was fully restored in the VCaP xenografts that relapsed after castration, coincident with AR reactivation. AR reactivation in the relapsed xenografts was also associated with marked increases in mRNA encoding AR and androgen synthetic enzymes. These results show that expression of TMPRSS2:ERG, similarly to other AR-regulated Genes, is restored in CRPC and may contribute to tumor progression.
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reactivation of androgen receptor regulated tmprss2 ERG Gene expression in castration resistant prostate cancer
Cancer Research, 2009Co-Authors: Hongyun Wang, Shaoyong Chen, Youyuan Xu, Steven P BalkAbstract:It seems clear that androgen receptor (AR)–regulated expression of the TMPRSS2:ERG fusion Gene plays an early role in prostate cancer (PC) development or progression, but the extent to which TMPRSS2:ERG is down-regulated in response to androgen deprivation therapy (ADT) and whether AR reactivates TMPRSS2:ERG expression in castration-resistant PC (CRPC) have not been determined. We show that ERG message levels in TMPRSS2:ERG fusion-positive CRPC are comparable with the levels in fusion Gene–positive primary PC, consistent with the conclusion that the TMPRSS2:ERG expression is reactivated by AR in CRPC. To further assess whether TMPRSS2:ERG expression is initially down-regulated in response to ADT, we examined VCaP cells, which express the TMPRSS2:ERG fusion Gene, and xenografts. ERG message and protein rapidly declined in response to removal of androgen in vitro and castration in vivo . Moreover, as observed in the clinical samples, ERG expression was fully restored in the VCaP xenografts that relapsed after castration, coincident with AR reactivation. AR reactivation in the relapsed xenografts was also associated with marked increases in mRNA encoding AR and androgen synthetic enzymes. These results show that expression of TMPRSS2:ERG , similarly to other AR-regulated Genes, is restored in CRPC and may contribute to tumor progression. [Cancer Res 2009;69(15):6027–32]
Jan Trapman - One of the best experts on this subject based on the ideXlab platform.
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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
Cancer Research, 2006Co-Authors: Karin G. Hermans, Ronald Van Marion, Herman Van Dekken, Guido Jenster, Wytske M Van Weerden, Jan TrapmanAbstract: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. (Cancer Res 2006; 66(22): 10658-63)
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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
Cancer Research, 2006Co-Authors: Karin G. Hermans, Guido Jenster, Ronald Van Marion, Herman Van Dekken, Wytske M Van Weerden, Jan TrapmanAbstract: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.
Gerhardt Attard - One of the best experts on this subject based on the ideXlab platform.
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improvements in radiographic progression free survival stratified by ERG Gene status in metastatic castration resistant prostate cancer patients treated with abiraterone acetate
Clinical Cancer Research, 2015Co-Authors: Gerhardt Attard, Anthony M Joshua, Johann S De Bono, Christopher J Logothetis, Karim Fizazi, Som D Mukherjee, D Schrijvers, Alfons J M Van Den Eertwegh, Weimin Li, Arturo MolinaAbstract:Purpose: Gene fusions leading to androgen receptor–modulated ERG overexpression occur in up to 70% of metastatic castration-resistant prostate cancers (mCRPC). We assessed the association between ERG rearrangement status and clinical benefit from abiraterone acetate. Experimental Design: COU-AA-302 is a phase III trial comparing abiraterone acetate and prednisone versus prednisone in chemotherapy-naive mCRPC. ERG status was evaluated by FISH on archival tumors. End points included radiographic progression-free survival (rPFS), time to PSA progression (TTPP), rate of ≥50% PSA decline from baseline, and overall survival (OS). Cox regression was used to evaluate association with time-to-event measures and Cochran–Mantel–Haenszel for PSA response. Results: ERG status was defined for 348 of 1,088 intention-to-treat patients. ERG was rearranged in 121 of 348 patients with confirmed ERG status (35%). Cancers with an ERG fusion secondary to deletion of 21q22 and increased copy number of fusion sequences (class 2+ Edel) had a greater improvement in rPFS after abiraterone acetate and prednisone [22 vs. 5.4 months; HR (95% confidence interval, CI), 0.31 (0.15–0.68); P = 0.0033] than cancers with no ERG fusion [16.7 vs. 8.3 months; 0.53 (0.38–0.74); P = 0.0002] or other classes of ERG rearrangement. There was also greater benefit in this subgroup for TTPP. Conclusions: Both ERG -rearranged and wild-type cancers had a significant improvement in rPFS with abiraterone acetate and prednisone in the COU-AA-302 trial. However, our data suggest that 2+ Edel cancers, accounting for 15% of all mCRPC patients and previously associated with a worse outcome, derived the greatest benefit. Clin Cancer Res; 21(7); 1621–7. ©2015 AACR .
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characterization of ERG ar and pten Gene status in circulating tumor cells from patients with castration resistant prostate cancer
Cancer Research, 2009Co-Authors: Gerhardt Attard, Joost F Swennenhuis, David Olmos, Alison Reid, Elaine Vickers, Roger Ahern, Rianne Levink, Frank A W Coumans, Joana Moreira, Ruth RiisnaesAbstract:Hormone-driven expression of the ERG oncoGene after fusion with TMPRSS2 occurs in 30% to 70% of therapy-naive prostate cancers. Its relevance in castration-resistant prostate cancer (CRPC) remains controversial as ERG is not expressed in some TMPRSS2-ERG androgen-independent xenograft models. However, unlike these models, CRPC patients have an increasing prostate-specific antigen, indicating active androgen receptor signaling. Here, we collected blood every month from 89 patients (54 chemotherapy-naive patients and 35 docetaxel-treated patients) treated in phase I/phase II clinical trials of an orally available, highly specific CYP17 inhibitor, abiraterone acetate, that ablates the synthesis of androgens and estrogens that drive TMPRSS2-ERG fusions. We isolated circulating tumor cells (CTC) by anti-epithelial cell adhesion molecule immunomagnetic selection followed by cytokeratin and CD45 immunofluorescence and 4',6-diamidino-2-phenylindole staining. We used multicolor fluorescence in situ hybridization to show that CRPC CTCs, metastases, and prostate tissue invariably had the same ERG Gene status as therapy-naive tumors (n=31). We then used quantitative reverse transcription-PCR to show that ERG expression was maintained in CRPC. We also observed homoGeneity in ERG Gene rearrangement status in CTCs (n=48) in contrast to significant heteroGeneity of AR copy number gain and PTEN loss, suggesting that rearrangement of ERG may be an earlier event in prostate carcinoGenesis. We finally report a significant association between ERG rearrangements in therapy-naive tumors, CRPCs, and CTCs and magnitude of prostate-specific antigen decline (P=0.007) in CRPC patients treated with abiraterone acetate. These data confirm that CTCs are malignant in origin and indicate that hormone-regulated expression of ERG persists in CRPC.
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characterization of ERG ar and pten Gene status in circulating tumor cells from patients with castration resistant prostate cancer
Cancer Research, 2009Co-Authors: Gerhardt Attard, Joost F Swennenhuis, David Olmos, Alison Reid, Elaine Vickers, Roger Ahern, Rianne Levink, Frank A W Coumans, Joana Moreira, Ruth RiisnaesAbstract:Hormone-driven expression of the ERG oncoGene after fusion with TMPRSS2 occurs in 30% to 70% of therapy-naive prostate cancers. Its relevance in castration-resistant prostate cancer (CRPC) remains controversial as ERG is not expressed in some TMPRSS2-ERG androgen-independent xenograft models. However, unlike these models, CRPC patients have an increasing prostate-specific antigen, indicating active androgen receptor signaling. Here, we collected blood every month from 89 patients (54 chemotherapy-naive patients and 35 docetaxel-treated patients) treated in phase I/phase II clinical trials of an orally available, highly specific CYP17 inhibitor, abiraterone acetate, that ablates the synthesis of androgens and estrogens that drive TMPRSS2-ERG fusions. We isolated circulating tumor cells (CTC) by anti–epithelial cell adhesion molecule immunomagnetic selection followed by cytokeratin and CD45 immunofluorescence and 4′,6-diamidino-2-phenylindole staining. We used multicolor fluorescence in situ hybridization to show that CRPC CTCs, metastases, and prostate tissue invariably had the same ERG Gene status as therapy-naive tumors ( n = 31). We then used quantitative reverse transcription–PCR to show that ERG expression was maintained in CRPC. We also observed homoGeneity in ERG Gene rearrangement status in CTCs ( n = 48) in contrast to significant heteroGeneity of AR copy number gain and PTEN loss, suggesting that rearrangement of ERG may be an earlier event in prostate carcinoGenesis. We finally report a significant association between ERG rearrangements in therapy-naive tumors, CRPCs, and CTCs and magnitude of prostate-specific antigen decline ( P = 0.007) in CRPC patients treated with abiraterone acetate. These data confirm that CTCs are malignant in origin and indicate that hormone-regulated expression of ERG persists in CRPC. [Cancer Res 2009;69(7):2912–8]
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duplication of the fusion of tmprss2 to ERG sequences identifies fatal human prostate cancer
Oncogene, 2008Co-Authors: Gerhardt Attard, Jeremy Clark, Penny Flohr, C S Foster, L Ambroisine, G Fisher, Gyula Kovacs, Daniel M Berney, A Fletcher, William L GeraldAbstract:New predictive markers for managing prostate cancer are urgently required because of the highly variable natural history of this disease. At the time of diagnosis, Gleason score provides the gold standard for assessing the aggressiveness of prostate cancer. However, the recent discovery of TMPRSS2 fusions to the ERG Gene in prostate cancer raises the possibility of using alterations at the ERG locus as additional mechanism-based prognostic indicators. Fluorescence in situ hybridization (FISH) assays were used to assess ERG Gene status in a cohort of 445 prostate cancers from patients who had been conservatively managed. The FISH assays detected separation of 5′ (labelled green) and 3′ (labelled red) ERG sequences, which is a consequence of the TMPRSS2–ERG fusion, and additionally identify interstitial deletion of genomic sequences between the tandemly located TMPRSS2 and ERG Gene sequences on chromosome 21. Cancers lacking ERG alterations exhibited favourable cause-specific survival (90% survival at 8 years). We identify a novel category of prostate cancers, characterized by duplication of the fusion of TMPRSS2 to ERG sequences together with interstitial deletion of sequences 5′ to ERG (called ‘2+Edel’), which by comparison exhibited extremely poor cause-specific survival (hazard ratio=6.10, 95% confidence ratio=3.33–11.15, P<0.001, 25% survival at 8 years). In multivariate analysis, ‘2+Edel’ provided significant prognostic information (P=0.003) in addition to that provided by Gleason score and prostate-specific antigen level at diagnosis. Other individual categories of ERG alteration were associated with intermediate or good prognosis. We conclude that determination of ERG Gene status, including duplication of the fusion of TMPRSS2 to ERG sequences in 2+Edel, allows stratification of prostate cancer into distinct survival categories.
Antonio Lopezbeltran - One of the best experts on this subject based on the ideXlab platform.
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tmprss2 ERG Gene fusion is rare compared to pten deletions in stage t1a prostate cancer
Molecular Carcinogenesis, 2017Co-Authors: Kurt W Fisher, Gregory T Maclennan, Rodolfo Montironi, Mingsheng Wang, Shaobo Zhang, Sean R Williamson, Lisha Wang, Lee Ann Baldrige, Jonas Y Wang, Antonio LopezbeltranAbstract:T1a prostate cancers (cancer found incidentally in transurethral resection, <5% of the tissue) are indolent tumors of the transition zone. The overexpression of ERG and the inactivation of PTEN have been shown to be important drivers of carcinoGenesis in large series of prostate cancer, but the Genetics of transition zone tumors have not been well characterized. We evaluated the status of ERG and PTEN in formalin-fixed paraffin-embedded tissue using immunohistochemical and FISH analysis in 54 T1a transition zone tumors. The protein expression of ERG was determined using a rabbit monoclonal antibody and nuclear staining was scored as positive or negative. The genomic status of ERG was determined using three colored FISH using an ERG-TMPRSS2 tri-color probe set. The protein expression of PTEN was determined using a rabbit monoclonal antibody and cytoplasmic, and nuclear staining was scored as positive or negative. The genomic status of PTEN was determined using dual color FISH with a PTEN probe and a CEP10 probe. We found ERG rearrangement in 2 of 54 tumors (4%), one with protein overexpression by immunohistochemistry. PTEN inactivation was seen in 13 of 54 tumors (24%). Nine of the 13 PTEN alleles were inactivated by hemizygous deletion. No homozygous PTEN deletion was observed. PTEN deletion and ERG rearrangement were mutually exclusive. ERG rearrangement was rare compared to peripheral zone tumors and to PTEN inactivation in T1a transition zone tumors. © 2016 Wiley Periodicals, Inc.
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atypical adenomatous hyperplasia of prostate lacks tmprss2 ERG Gene fusion
The American Journal of Surgical Pathology, 2013Co-Authors: Liang Cheng, Darrell D Davidson, Gregory T Maclennan, Antonio Lopezbeltran, Rodolfo Montironi, Mingsheng Wang, Lee Ann Baldridge, Shaobo ZhangAbstract:: Atypical adenomatous hyperplasia (AAH) is a distinct entity in prostate pathology, defined as a well-circumscribed lobule of closely packed crowded small glands or acini. Although it has been proposed as a precursor lesion to prostate cancer, the biological nature of AAH is currently uncertain. The TMPRSS2-ERG fusion Gene is a common recurrent chromosomal rearrangement in prostate cancer and in its precursor lesion, prostatic intraepithelial neoplasia. The prevalence of TMPRSS2-ERG alteration in AAH is unknown. Fifty-five separate prostate specimens containing AAH were investigated by fluorescence in situ hybridization and immunohistochemistry for TMPRSS2-ERG rearrangement. TMPRSS2-ERG rearrangements were not identified in AAH either by fluorescence in situ hybridization or by immunohistochemistry.
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frequent tmprss2 ERG rearrangement in prostatic small cell carcinoma detected by fluorescence in situ hybridization the superiority of fluorescence in situ hybridization over ERG immunohistochemistry
Human Pathology, 2013Co-Authors: Lindsay A Schelling, Antonio Lopezbeltran, Rodolfo Montironi, Mingsheng Wang, Shaobo Zhang, Jiaoti Huang, Sean R Williamson, Jorge L Yao, Robert E Emerson, Muhammad T IdreesAbstract:Small cell carcinoma of the prostate is both morphologically and immunohistochemically similar to small cell carcinoma of other organs such as the urinary bladder or lung. TMPRSS2-ERG Gene fusion appears to be a highly specific alteration in prostatic carcinoma that is frequently shared by small cell carcinoma. In adenocarcinoma, immunohistochemistry for the ERG protein product has been reported to correlate well with the presence of the Gene fusion, although in prostatic small cell carcinoma, this relationship is not completely understood. We evaluated 54 cases of small cell carcinoma of the prostate and compared TMPRSS2-ERG Gene fusion status by fluorescence in situ hybridization (FISH) to immunohistochemical staining with antibody to ERG. Of 54 cases of prostatic small cell carcinoma, 26 (48%) were positive for TMPRSS2-ERG Gene fusion by FISH and 12 (22%) showed overexpression of ERG protein by immunohistochemistry. Of the 26 cases positive by FISH, 11 were also positive for ERG protein by immunohistochemistry. One tumor was positive by immunohistochemistry but negative by FISH. Urinary bladder small cell carcinoma (n = 25) showed negative results by both methods; however, 2 of 14 small cell carcinomas of other organs (lung, head, and neck) showed positive immunohistochemistry but negative FISH. Positive staining for ERG by immunohistochemistry is present in a subset of prostatic small cell carcinomas and correlates with the presence of TMPRSS2-ERG Gene fusion. Therefore, it may be useful in confirming prostatic origin when molecular testing is not accessible. However, sensitivity and specificity of ERG immunohistochemistry in small cell carcinoma are decreased compared to FISH.
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ERG tmprss2 rearrangement is shared by concurrent prostatic adenocarcinoma and prostatic small cell carcinoma and absent in small cell carcinoma of the urinary bladder evidence supporting monoclonal origin
Modern Pathology, 2011Co-Authors: Sean R Williamson, Gregory T Maclennan, Antonio Lopezbeltran, Rodolfo Montironi, Shaobo Zhang, Jiaoti Huang, Jorge L Yao, Steven S Shen, Adeboye O Osunkoya, Liang ChengAbstract:Prostatic carcinoma is a heteroGeneous disease with frequent multifocality and variability in morphology. Particularly, prostatic small cell carcinoma is a rare variant with aggressive behavior. Distinction between small cell carcinoma of the prostate and urinary bladder may be challenging, especially in small biopsy specimens without associated prostatic adenocarcinoma or urothelial carcinoma. Recently, Gene fusions between ETS Genes, particularly ETS-related Gene (ERG), and transmembrane protease, serine 2 (TMPRSS2) have been identified as a frequent event in prostate cancer. Thus, molecular methods may be helpful in determining the primary site of small cell carcinoma. Thirty cases of prostatic small cell carcinoma from the authors' archives were studied, among which 13 had concurrent prostatic adenocarcinoma. Tricolor fluorescence in situ hybridization (FISH) was performed on formalin-fixed paraffin-embedded tissue sections with a probe cocktail for 3'/5' ERG and TMPRSS2. Cases of small cell carcinoma of the bladder and conventional prostatic adenocarcinoma (25 each) were also tested as controls. ERG Gene alterations were found only in prostate malignancies and not in benign prostatic tissue or bladder small cell carcinoma. TMPRSS2-ERG Gene fusion was found in 47% (14/30) of prostatic small cell carcinoma. Of cases with concurrent prostatic adenocarcinoma, 85% (11/13) had identical findings in both components. In 20% of rearranged cases, the ERG abnormality was associated with 5' ERG deletion. In 17% (5/30) of cases, gain of the 21q22 locus was present. Two cases showed discordant aberrations in the small cell carcinoma and adenocarcinoma, one with deletion of 5' ERG and one with gain of chromosome 21q, both in only the adenocarcinoma component. Small cell carcinoma of the prostate demonstrates TMPRSS2-ERG rearrangement with comparable frequency to prostatic adenocarcinoma. In cases with concurrent adenocarcinoma and small cell carcinoma, the majority showed identical abnormalities in both components, indicating a likely common clonal origin. Discordant alterations were present in rare cases, suggesting that acquisition of additional Genetic changes in multifocal tumors may be responsible for disease progression to a more aggressive phenotype. TMPRSS2-ERG fusion is absent in bladder small cell carcinoma, supporting the utility of FISH in distinguishing prostate from bladder primary tumors and identifying metastatic small cell carcinoma of unknown origin.