The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
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.
Scott A Tomlins - One of the best experts on this subject based on the ideXlab platform.
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novel rna hybridization method for the in situ detection of etv1 etv4 and etv5 gene fusions in prostate cancer
Applied Immunohistochemistry & Molecular Morphology, 2014Co-Authors: Lakshmi P Kunju, Shannon Carskadon, Scott A Tomlins, Javed Siddiqui, Arul M Chinnaiyan, Nallasivam PalanisamyAbstract:: The genetic basis of 50% to 60% of prostate cancer (PCa) is attributable to rearrangements in E26 transformation-specific (ETS) (ERG, ETV1, ETV4, and ETV5), BRAF, and RAF1 genes and overexpression of SPINK1. The development and validation of reliable detection methods are warranted to classify various molecular subtypes of PCa for diagnostic and prognostic purposes. ETS gene rearrangements are typically detected by fluorescence in situ hybridization and reverse-transcription polymerase chain reaction methods. Recently, monoclonal antibodies against ERG have been developed that detect the truncated ERG protein in immunohistochemical assays where staining levels are strongly correlated with ERG rearrangement status by fluorescence in situ hybridization. However, specific antibodies for ETV1, ETV4, and ETV5 are unavailable, challenging their clinical use. We developed a novel RNA in situ hybridization-based assay for the in situ detection of ETV1, ETV4, and ETV5 in formalin-fixed paraffin-embedded tissues from prostate needle biopsies, prostatectomy, and metastatic PCa specimens using RNA probes. Further, with combined RNA in situ hybridization and immunohistochemistry we identified a rare subset of PCa with dual ETS gene rearrangements in collisions of independent tumor foci. The high specificity and sensitivity of RNA in situ hybridization provides an alternate method enabling bright-field in situ detection of ETS gene aberrations in routine clinically available PCa specimens.
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characterization of tmprss2 ets gene aberrations in androgen independent metastatic prostate cancer
Cancer Research, 2008Co-Authors: Scott A Tomlins, Anjana Menon, Mark A Rubin, Rajal B Shah, Xuhong Cao, Kenneth J Pienta, Arul M ChinnaiyanAbstract:Recurrent gene fusions between the androgen-regulated gene TMPRSS2 and the ETS transcription factor family members ERG, ETV1, and ETV4 have been identified as a critical event in prostate cancer development. In this study, we characterized the prevalence and diversity of these rearrangements in hormone-refractory metastatic prostate cancer. We used a fluorescence in situ hybridization (FISH) split probe strategy to comprehensively evaluate TMPRSS2-ETS aberrations across 97 nonosseous metastatic sites of prostate cancer from 30 rapid autopsies of men who died of androgen-independent disease. Tissue microarrays were constructed representing multiple metastatic sites from each patient, and split signal FISH probes for TMPRSS2, ERG, ETV1, and ETV4 were used to assess for TMPRSS2-ETS rearrangements. In patients exhibiting these aberrations, multiple sites from an individual case harbored the same gene fusion molecular subtype suggesting clonal expansion of disease. The most common prostate cancer gene fusion, TMPRSS2-ERG, can be generated by the mechanism of interstitial deletion (Edel) about 39% to 60% of the time in clinically localized disease. Interestingly, we observed that all of the androgen-independent metastatic prostate cancer sites harboring TMPRSS2-ERG were associated with Edel. These findings suggest that TMPRSS2-ERG with Edel is an aggressive and, in this study, uniformly lethal molecular subtype of prostate cancer associated with androgen-independent disease.
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characterization of tmprss2 etv5 and slc45a3 etv5 gene fusions in prostate cancer
Cancer Research, 2008Co-Authors: Beth E Helgeson, Scott A Tomlins, Bharathi Laxman, Xuhong Cao, Qi Cao, Nameeta Shah, John R Prensner, Nirmish Singla, James E Montie, Sooryanarayana VaramballyAbstract:Recurrent gene fusions involving oncogenic ETS transcription factors (including ERG, ETV1, and ETV4) have been identified in a large fraction of prostate cancers. The most common fusions contain the 5′ untranslated region of TMPRSS2 fused to ERG. Recently, we identified additional 5′ partners in ETV1 fusions, including TMPRSS2, SLC45A3, HERV-K_22q11.23, C15ORF21, and HNRPA2B1. Here, we identify ETV5 as the fourth ETS family member involved in recurrent gene rearrangements in prostate cancer. Characterization of two cases with ETV5 outlier expression by RNA ligase–mediated rapid amplification of cDNA ends identified one case with a TMPRSS2:ETV5 fusion and one case with a SLC45A3:ETV5 fusion. We confirmed the presence of these fusions by quantitative PCR and fluorescence in situ hybridization. In vitro recapitulation of ETV5 overexpression induced invasion in RWPE cells, a benign immortalized prostatic epithelial cell line. Expression profiling and an integrative molecular concepts analysis of RWPE-ETV5 cells also revealed the induction of an invasive transcriptional program, consistent with ERG and ETV1 overexpression in RWPE cells, emphasizing the functional redundancy of ETS rearrangements. Together, our results suggest that the family of 5′ partners previously identified in ETV1 gene fusions can fuse with other ETS family members, suggesting numerous rare gene fusion permutations in prostate cancer. [Cancer Res 2008;68(1):73–80]
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recurrent gene fusions in prostate cancer etv1 class of fusions
Cancer Epidemiology and Prevention Biomarkers, 2007Co-Authors: Saravana M Dhanasekaran, Scott A Tomlins, Bharathi Laxman, Beth E Helgeson, Chandan Kumarsinha, Anjana Menon, Xiaojun Jing, David Morris, Jindan YuAbstract:CN02-04 The discovery of BCR-ABL1 gene fusion in chronic myelogenous leukemia helped to understand the role of chromosomal aberrations in carcinogenesis and has also served as a target for effective therapeutic intervention. Recently, we reported the discovery of recurrent gene fusion events in prostate cancer, a common epithelial carcinoma. These gene fusions juxtaposed the 59 untranslated region of the androgen-regulated gene TMPRSS2 and the ETS (E26 transformation-specific) family genes ERG, ETV1 or ETV4 in most prostate cancers. Characterization of prostate tumors that overexpress ETV1 has now identified several new 59 fusion partners. The list of novel 5’ partners include, untranslated regions from a prostate-specific androgen-induced gene (SLC45A3) and an endogenous retroviral element (HERV-K_22q11.23), a prostate-specific androgen-repressed gene (C15orf21), and a strongly expressed housekeeping gene (HNRPA2B1). Among the two ETV1 overexpressing prostate cancer cell lines, LNCaP and MDA-PCa 2B, we observed a rearrangement of the entire ETV1 locus (7p21) to a 1.5-megabase prostate-specific region at 14q13.3-14q21.1 in both LNCaP cells (cryptic insertion) and MDA-PCa 2B cells (balanced translocation). Functional aspects of ETV1 overexpression was studied in vitro and in vivo. In both benign prostate cells and in the mouse prostate ETV1 overexpression confered neoplastic phenotypes. Thus, identification of distinct classes of ETS gene rearrangements demonstrates that dormant oncogenes can be activated in prostate cancer by juxtaposition to tissue-specific or ubiquitously active genomic loci.
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Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer
Nature, 2007Co-Authors: Scott A Tomlins, Bharathi Laxman, Beth E Helgeson, Saravana M Dhanasekaran, Anjana Menon, Xiaojun Jing, Xuhong Cao, David S. Morris, Qi Cao, Bo HanAbstract:Recently, we identified recurrent gene fusions involving the 5' untranslated region of the androgen-regulated gene TMPRSS2 and the ETS (E26 transformation-specific) family genes ERG, ETV1 or ETV4 in most prostate cancers. Whereas TMPRSS2-ERG fusions are predominant, fewer TMPRSS2-ETV1 cases have been identified than expected on the basis of the frequency of high (outlier) expression of ETV1 (refs 3-13). Here we explore the mechanism of ETV1 outlier expression in human prostate tumours and prostate cancer cell lines. We identified previously unknown 5' fusion partners in prostate tumours with ETV1 outlier expression, including untranslated regions from a prostate-specific androgen-induced gene (SLC45A3) and an endogenous retroviral element (HERV-K_22q11.23), a prostate-specific androgen-repressed gene (C15orf21), and a strongly expressed housekeeping gene (HNRPA2B1). To study aberrant activation of ETV1, we identified two prostate cancer cell lines, LNCaP and MDA-PCa 2B, that had ETV1 outlier expression. Through distinct mechanisms, the entire ETV1 locus (7p21) is rearranged to a 1.5-megabase prostate-specific region at 14q13.3-14q21.1 in both LNCaP cells (cryptic insertion) and MDA-PCa 2B cells (balanced translocation). Because the common factor of these rearrangements is aberrant ETV1 overexpression, we recapitulated this event in vitro and in vivo, demonstrating that ETV1 overexpression in benign prostate cells and in the mouse prostate confers neoplastic phenotypes. Identification of distinct classes of ETS gene rearrangements demonstrates that dormant oncogenes can be activated in prostate cancer by juxtaposition to tissue-specific or ubiquitously active genomic loci. Subversion of active genomic regulatory elements may serve as a more generalized mechanism for carcinoma development. Furthermore, the identification of androgen-repressed and insensitive 5' fusion partners may have implications for the anti-androgen treatment of advanced prostate cancer.
Michal Michal - One of the best experts on this subject based on the ideXlab platform.
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mammary analogue secretory carcinoma of salivary glands molecular analysis of 25 ETV6 gene rearranged tumors with lack of detection of classical ETV6 ntrk3 fusion transcript by standard rt pcr report of 4 cases harboring ETV6 x gene fusion
The American Journal of Surgical Pathology, 2016Co-Authors: Alena Skalova, Tomas Vanecek, Roderick H W Simpson, Jan Laco, Hanna Majewska, Martina Baneckova, Petr Steiner, Michal MichalAbstract:ETV6 gene abnormalities are well described in tumor pathology. Many fusion partners of ETV6 have been reported in a variety of epithelial and hematological malignancies. In salivary gland tumor pathology, however, the ETV6-NTRK3 translocation is specific for mammary analogue secretory carcinoma (MAS
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mammary analogue secretory carcinoma of salivary glands molecular analysis of 25 ETV6 gene rearranged tumors with lack of detection of classical ETV6 ntrk3 fusion transcript by standard rt pcr report of 4 cases harboring ETV6 x gene fusion
The American Journal of Surgical Pathology, 2016Co-Authors: Alena Skalova, Tomas Vanecek, Roderick H W Simpson, Jan Laco, Hanna Majewska, Martina Baneckova, Petr Steiner, Michal MichalAbstract:ETV6 gene abnormalities are well described in tumor pathology. Many fusion partners of ETV6 have been reported in a variety of epithelial and hematological malignancies. In salivary gland tumor pathology, however, the ETV6-NTRK3 translocation is specific for mammary analogue secretory carcinoma (MASC), and has not been documented in any other salivary tumor type. The present study comprised a clinical and molecular analysis of 25 cases morphologically and immunohistochemically typical of MASC. They all also displayed the ETV6 rearrangement as visualized by fluorescent in situ hybridization but lacked the classical ETV6-NTRK3 fusion transcript by standard reverse-transcriptase-polymerase chain reaction. In 4 cases, the classical fusion transcript was found by more sensitive, nested reverse-transcription-polymerase chain reaction. Five other cases harbored atypical fusion transcripts as detected by both standard and nested reverse-transcription-polymerase chain reaction. In addition, fluorescent in situ hybridization with an NTRK3 break-apart probe was also performed; rearrangement of NTRK3 gene was detected in 16 of 25 cases. In 3 other cases, the tissue was not analyzable, and in 2 further cases analysis could not be performed because of a lack of appropriate tissue material. Finally, in the 4 remaining cases whose profile was NTRK3 split-negative and ETV6 split-positive, unknown (non-NTRK) genes appeared to fuse with ETV6 (ETV6-X fusion). In looking for possible fusion partners, analysis of rearrangement of other kinase genes known to fuse with ETV6 was also performed, but without positive results. Although numbers were small, correlating the clinico-pathologic features of the 4 ETV6-X fusion tumors and 5 MASC cases with atypical fusion transcripts raises the possibility of that they may behave more aggressively.
Yuko Sato - One of the best experts on this subject based on the ideXlab platform.
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flt3 is fused to ETV6 in a myeloproliferative disorder with hypereosinophilia and a t 12 13 p13 q12 translocation
Leukemia, 2006Co-Authors: Hoang Anh Vu, Michihiko Masuda, Phan Thi Xinh, Yoshiyuki Sakaki, Toshiko Motoji, Atsushi Toyoda, Katsushi Tokunaga, Yuko SatoAbstract:The FMS-like tyrosine kinase 3 (FLT3) gene, belonging to the receptor tyrosine kinase (TK) subclass III family, plays an important role in normal hematopoiesis and is one of the most frequently mutated genes in hematologic malignancies as well as an attractive target for directed inhibition. Activating mutations of this gene, including internal tandem duplication in the juxtamembrane (JM) domain and point mutations in the TK domain, are found in approximately one-third of patients with acute myeloid leukemia and in a smaller subset of patients with acute lymphoblastic leukemia. We report here that FLT3 may contribute to leukemogenesis in a patient with myeloproliferative disorder and a t(12;13)(p13;q12) translocation through generating a fusion gene with the ETS variant gene 6 (ETV6) gene. ETV6 has been reported to fuse to various partner genes, including TK and transcription factors. Both ETV6/FLT3 and reciprocal FLT3/ETV6 transcripts were detected in the patient mRNA by reverse transcriptase-polymerase chain reaction. At the protein level, however, only ETV6/FLT3 products were expressed. Among them, one retains the helix-loop-helix (HLH) oligomerization domain of ETV6 and the JM as well as TK domain of FLT3. FLT3 receptor in leukemic cells might be inappropriately activated through dimerization by HLH domain of ETV6, which consequently interfered with proliferation and differentiation of hematopoietic cells.
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flt3 is fused to ETV6 in a myeloproliferative disorder with hypereosinophilia and a t 12 13 p13 q12 translocation
Leukemia, 2006Co-Authors: Hoang Anh Vu, Michihiko Masuda, Phan Thi Xinh, Yoshiyuki Sakaki, Toshiko Motoji, Atsushi Toyoda, Katsushi Tokunaga, Yuko SatoAbstract:The FMS-like tyrosine kinase 3 (FLT3) gene, belonging to the receptor tyrosine kinase (TK) subclass III family, plays an important role in normal hematopoiesis and is one of the most frequently mutated genes in hematologic malignancies as well as an attractive target for directed inhibition. Activating mutations of this gene, including internal tandem duplication in the juxtamembrane (JM) domain and point mutations in the TK domain, are found in approximately one-third of patients with acute myeloid leukemia and in a smaller subset of patients with acute lymphoblastic leukemia. We report here that FLT3 may contribute to leukemogenesis in a patient with myeloproliferative disorder and a t(12;13)(p13;q12) translocation through generating a fusion gene with the ETS variant gene 6 (ETV6) gene. ETV6 has been reported to fuse to various partner genes, including TK and transcription factors. Both ETV6/FLT3 and reciprocal FLT3/ETV6 transcripts were detected in the patient mRNA by reverse transcriptase-polymerase chain reaction. At the protein level, however, only ETV6/FLT3 products were expressed. Among them, one retains the helix-loop-helix (HLH) oligomerization domain of ETV6 and the JM as well as TK domain of FLT3. FLT3 receptor in leukemic cells might be inappropriately activated through dimerization by HLH domain of ETV6, which consequently interfered with proliferation and differentiation of hematopoietic cells.
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a new ETV6 tel partner gene arg abl related gene or abl2 identified in an aml m3 cell line with a t 1 12 q25 p13 translocation
Blood, 2000Co-Authors: Yoshimi Iijima, Yoshiyuki Sakaki, Takashi Ito, Tsuneyuki Oikawa, Mariko Eguchi, Minenori Eguchiishimae, Nanao Kamada, Kenji Kishi, Shigetaka Asano, Yuko SatoAbstract:The ETV6/TEL gene has been reported to fuse to PDGFRβb MDS1/EVI1 , BTL , ACS2 , STL , JAK2 , ABL , CDX2 , TRKC , AML1, and MN1 . Among them, PDGFRβ , ABL , JAK2, and TRKC are tyrosine kinases (TK). We identified a novel ETV6 partner gene, ARG ( ABL- related gene or ABL2 ), another TK gene in a cell line established from a patient with acute myelogenous leukemia (AML-M3) with a t(15;17)(q22;q11.2) and a t(1;12)(q25;p13), which has the remarkable feature to differentiate to mature eosinophils in culture with all-trans retinoic acid and cytokines. The ETV6/ARG transcripts consisted of exon 1 to 5 of ETV6 and the 3′ portion of ARG starting from exon 1B or exon 2, resulting in an open reading frame for a fusion protein consisting of the entire PNT oligomerization domain of ETV6 and all of the functional domains of ARG including the TK domain. This is the same protein structure as identified in the other ETV6 TK fusion proteins. The reciprocal ARG/ETV6 transcript was not expressed, and the normal ETV6 allele was not deleted or rearranged. Although the ABL is known to be involved in various human malignancies, ARG has not been involved in human malignancies despite its high homology to ABL . Thus, this is the first report showing involvement of ARG in human leukemia. The ETV6/ARG protein may be involved in the unique differentiation capacity of this cell line.
Karin G. Hermans - 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.
