The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Jacques Lapointe - One of the best experts on this subject based on the ideXlab platform.
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a variant tmprss2 isoform and erg Fusion Product in prostate cancer with implications for molecular diagnosis
Modern Pathology, 2007Co-Authors: Melinda A Miller, Jacques Lapointe, Young Ho Kim, Gulsah Kaygusuz, Matt Van De Rijn, David G Huntsman, James D Brooks, Jonathan R PollackAbstract:Prostate cancer is the most commonly diagnosed cancer among men in the United States. Recently, Fusion of TMPRSS2 with ETS family oncogenic transcription factors has been identified as a common molecular alteration in prostate cancer, where most often the rearrangement places ERG under the androgen-regulated transcriptional control of TMPRSS2. Here, we carried out rapid amplification of cDNA ends (RACE) on a prostate cancer specimen carrying an atypical aberration discovered by array-based comparative genomic hybridization (array CGH), suggesting an alternative Fusion partner of ERG. We identified novel transcribed sequences fused to ERG, mapping 4 kb upstream of the TMPRSS2 start site. The sequences derive from an apparent second TMPRSS2 isoform, which we found also expressed in some prostate tumors, suggesting similar androgen-regulated control. In a reverse transcription-polymerase chain reaction (RT-PCR)-based survey of 63 prostate tumor specimens (54 primary and nine lymph node metastases), 44 (70%) cases expressed either the known or novel variant TMPRSS2-ERG Fusion, 28 (44%) expressed both, 10 (16%) expressed only the known, and notably six (10%) expressed only the variant isoform Fusion. In this specimen set, the presence of a TMPRSS2-ERG Fusion showed no statistical association with tumor stage, Gleason grade or recurrence-free survival. Nonetheless, the discovery of a novel variant TMPRSS2 isoform-ERG Fusion adds to the characterization of ETS-family rearrangements in prostate cancer, and has important implications for the accurate molecular diagnosis of TMPRSS2-ETS Fusions.
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a variant tmprss2 isoform and erg Fusion Product in prostate cancer with implications for molecular diagnosis
Modern Pathology, 2007Co-Authors: Melinda A Miller, Jacques Lapointe, Gulsah Kaygusuz, David G Huntsman, Chunde Li, Matt Van De Rijn, James D BrooksAbstract:A variant TMPRSS2 isoform and ERG Fusion Product in prostate cancer with implications for molecular diagnosis
Gulsah Kaygusuz - One of the best experts on this subject based on the ideXlab platform.
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a variant tmprss2 isoform and erg Fusion Product in prostate cancer with implications for molecular diagnosis
Modern Pathology, 2007Co-Authors: Melinda A Miller, Jacques Lapointe, Young Ho Kim, Gulsah Kaygusuz, Matt Van De Rijn, David G Huntsman, James D Brooks, Jonathan R PollackAbstract:Prostate cancer is the most commonly diagnosed cancer among men in the United States. Recently, Fusion of TMPRSS2 with ETS family oncogenic transcription factors has been identified as a common molecular alteration in prostate cancer, where most often the rearrangement places ERG under the androgen-regulated transcriptional control of TMPRSS2. Here, we carried out rapid amplification of cDNA ends (RACE) on a prostate cancer specimen carrying an atypical aberration discovered by array-based comparative genomic hybridization (array CGH), suggesting an alternative Fusion partner of ERG. We identified novel transcribed sequences fused to ERG, mapping 4 kb upstream of the TMPRSS2 start site. The sequences derive from an apparent second TMPRSS2 isoform, which we found also expressed in some prostate tumors, suggesting similar androgen-regulated control. In a reverse transcription-polymerase chain reaction (RT-PCR)-based survey of 63 prostate tumor specimens (54 primary and nine lymph node metastases), 44 (70%) cases expressed either the known or novel variant TMPRSS2-ERG Fusion, 28 (44%) expressed both, 10 (16%) expressed only the known, and notably six (10%) expressed only the variant isoform Fusion. In this specimen set, the presence of a TMPRSS2-ERG Fusion showed no statistical association with tumor stage, Gleason grade or recurrence-free survival. Nonetheless, the discovery of a novel variant TMPRSS2 isoform-ERG Fusion adds to the characterization of ETS-family rearrangements in prostate cancer, and has important implications for the accurate molecular diagnosis of TMPRSS2-ETS Fusions.
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a variant tmprss2 isoform and erg Fusion Product in prostate cancer with implications for molecular diagnosis
Modern Pathology, 2007Co-Authors: Melinda A Miller, Jacques Lapointe, Gulsah Kaygusuz, David G Huntsman, Chunde Li, Matt Van De Rijn, James D BrooksAbstract:A variant TMPRSS2 isoform and ERG Fusion Product in prostate cancer with implications for molecular diagnosis
James D Brooks - One of the best experts on this subject based on the ideXlab platform.
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a variant tmprss2 isoform and erg Fusion Product in prostate cancer with implications for molecular diagnosis
Modern Pathology, 2007Co-Authors: Melinda A Miller, Jacques Lapointe, Young Ho Kim, Gulsah Kaygusuz, Matt Van De Rijn, David G Huntsman, James D Brooks, Jonathan R PollackAbstract:Prostate cancer is the most commonly diagnosed cancer among men in the United States. Recently, Fusion of TMPRSS2 with ETS family oncogenic transcription factors has been identified as a common molecular alteration in prostate cancer, where most often the rearrangement places ERG under the androgen-regulated transcriptional control of TMPRSS2. Here, we carried out rapid amplification of cDNA ends (RACE) on a prostate cancer specimen carrying an atypical aberration discovered by array-based comparative genomic hybridization (array CGH), suggesting an alternative Fusion partner of ERG. We identified novel transcribed sequences fused to ERG, mapping 4 kb upstream of the TMPRSS2 start site. The sequences derive from an apparent second TMPRSS2 isoform, which we found also expressed in some prostate tumors, suggesting similar androgen-regulated control. In a reverse transcription-polymerase chain reaction (RT-PCR)-based survey of 63 prostate tumor specimens (54 primary and nine lymph node metastases), 44 (70%) cases expressed either the known or novel variant TMPRSS2-ERG Fusion, 28 (44%) expressed both, 10 (16%) expressed only the known, and notably six (10%) expressed only the variant isoform Fusion. In this specimen set, the presence of a TMPRSS2-ERG Fusion showed no statistical association with tumor stage, Gleason grade or recurrence-free survival. Nonetheless, the discovery of a novel variant TMPRSS2 isoform-ERG Fusion adds to the characterization of ETS-family rearrangements in prostate cancer, and has important implications for the accurate molecular diagnosis of TMPRSS2-ETS Fusions.
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a variant tmprss2 isoform and erg Fusion Product in prostate cancer with implications for molecular diagnosis
Modern Pathology, 2007Co-Authors: Melinda A Miller, Jacques Lapointe, Gulsah Kaygusuz, David G Huntsman, Chunde Li, Matt Van De Rijn, James D BrooksAbstract:A variant TMPRSS2 isoform and ERG Fusion Product in prostate cancer with implications for molecular diagnosis
Frederic G Barr - One of the best experts on this subject based on the ideXlab platform.
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pdgf a pdgf rβ tgfβ3 and bone morphogenic protein 4 in desmoplastic small round cell tumors with ews wt1 gene Fusion Product and their role in stromal desmoplasia an immunohistochemical study
Modern Pathology, 2005Co-Authors: Paul J Zhang, John R Goldblum, Bruce R Pawel, Cyril Fisher, Theresa L Pasha, Frederic G BarrAbstract:PDGF-A, PDGF-R beta, TGF beta 3 and bone morphogenic protein-4 in desmoplastic small round cell tumors with EWS-WT1 gene Fusion Product and their role in stromal desmoplasia: an immunohistochemical study Histologically, desmoplastic small round cell tumor is composed of the characteristic neoplastic small round cells with divergent differentiation, and distinct desmoplastic stroma. Genetically, the tumor shows a characteristic 11; 22 translocation, involving the EWS gene on chromosome 22 and the WT1gene on chromosome 11 to produce an EWS- WT1 Fusion gene which generates a chimeric protein functioning as a novel transcription factor that activates expression of target genes such as PDGF- A. Expression of PDGF- A, a potent growth factor for fibroblasts, has been detected in desmoplastic small round cell tumors and has been linked to the characteristic desmoplasia in these tumors. Bone morphogenic proteins, which are members of the TGFbeta superfamily play a complex role in regulating cell growth and differentiation and bone formation but have not been evaluated in desmoplastic small round cell tumors. In all, 24 desmoplastic small round cell tumors with EWS- WT1 Fusion Product confirmed by RT- PCR analysis were evaluated for expression of PDGF- A, PDGF- Rbeta, TGFbeta3 and bone morphogenic protein- 4 by standard immunohistochemical methods with antigen retrieval on paraffin sections. Immunoreactivity was evaluated semiquantitively. Tumor- associated desmoplasia was quantified using a three- tier scale on hematoxylin- and eosin- stained sections. Desmoplastic small round cell tumors showed variable immunoreactivity with TGFbeta3 ( 21/ 24), BMP4 ( 14/ 21), PDGF- A ( 19/ 24) and PDGF- Rbeta ( 16/ 22). Less frequently, the stromal cells showed reactivity with TGFbeta3, PDGF- Rbeta and PDGF- A. Tumor- associated desmoplasia was prominent in eight, intermediate in seven and weak in nine cases. There was no correlation between tumor- associated desmoplasia and the markers tested except PDGF- A. In contrast to a previous study, our study showed that the level of PDGF- A expression inversely correlated with tumor-associated desmoplasia. Other targets of the EWS- WT1 transcription factor other than PDGF- A may be directly responsible for the prominent tumor- associated desmoplasia seen in desmoplastic small round cell tumor.
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Immunophenotype of Desmoplastic Small Round Cell Tumors as Detected in Cases with EWS-WT1 Gene Fusion Product
Modern Pathology, 2003Co-Authors: Paul J Zhang, John R Goldblum, Bruce R Pawel, Cyril Fisher, Teresa L Pasha, Frederic G BarrAbstract:Desmoplastic small round cell tumor is a rare tumor typically involving peritoneum. Although the histogenesis of desmoplastic small round cell tumor has yet to be elucidated, immunophenotypical and morphological analysis shows a characteristic divergent phenotype overlapping with other round cell tumors such as Ewing’s sarcoma/primitive neuroectodermal tumor, rhabdomyosarcoma, small cell mesothelioma, and carcinoma. Detection of the EWS-WT1 gene Fusion is characteristic of desmoplastic small round cell tumor and has been used reliably in tumor diagnosis. In this study, we evaluated the immunophenotype of 23 desmoplastic small round cell tumor cases with the EWS-WT1 gene Fusion Product identified by reverse transcription-polymerase chain reaction. Paraffin sections were stained with antibodies against calretinin, WT1 (C19), desmin, myoglobin, MyoD, Myf5, myogenin, placental alkaline phosphatase, cytokeratins, MIC2, HER2/neu and c-kit using standard immunohistochemical methods. Immunoreactivity was evaluated semiquantitively by light microscopy. Desmoplastic small round cell tumors showed reactivity with calretinin in 4/21, desmin in 21/23, myoglobin in 5/17, placental alkaline phosphatase in 17/21, HER2/neu in 7/18 (3+ in 1 and 1+ in 6), c-kit in 2/14, MIC2 in 13/23, WT1 in 16/23, CAM5.2 in 21/23, and AE1/3 in 16/23 cases. The most sensitive myogenic and epithelial markers are desmin and CAM 5.2. Although nuclear reactivity of the early myogenic regulatory factors (MyoD, myogenin, Myf5) was not detected, myoglobin immunoreactivity was present in 29% of desmoplastic small round cell tumors. HER2/neu overexpression (3+) and c-kit expression are uncommon in desmoplastic small round cell tumors. A panel of myogenic and epithelial markers should be used to detect the divergent phenotype in desmoplastic small round cell tumors, a key feature in the differential diagnosis. Detection of EWS-WT1 Fusion becomes critical for the diagnosis when the characteristic divergent phenotype cannot be detected immunohistochemically.
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Fusion genes resulting from alternative chromosomal translocations are overexpressed by gene specific mechanisms in alveolar rhabdomyosarcoma
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: Richard J Davis, Frederic G BarrAbstract:Chromosomal translocations identified in hematopoietic and solid tumors result in deregulated expression of protooncogenes or creation of chimeric proteins with tumorigenic potential. In the pediatric solid tumor alveolar rhabdomyosarcoma, a consistent t(2;13)(q35;q14) or variant t(1;13)(p36;q14) translocation generates PAX3-FKHR or PAX7-FKHR Fusion proteins, respectively. In this report, we demonstrate that in addition to functional alterations these translocations are associated with Fusion Product overexpression. Furthermore, PAX3-FKHR and PAX7-FKHR overexpression occurs by distinct mechanisms. Transcription of PAX3-FKHR is increased relative to wild-type PAX3 by a copy number-independent process. In contrast, PAX7-FKHR overexpression results from Fusion gene amplification. Thus, gene-specific mechanisms were selected to overexpress PAX3-FKHR and PAX7-FKHR in alveolar rhabdomyosarcoma, presumably due to differences in regulation between the wild-type loci. We postulate that these overexpression mechanisms ensure a critical level of gene Product for the oncogenic effects of these Fusions.
Arul M Chinnaiyan - One of the best experts on this subject based on the ideXlab platform.
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role of the tmprss2 erg gene Fusion in prostate cancer
Neoplasia, 2008Co-Authors: Scott A Tomlins, Bharathi Laxman, Beth E Helgeson, Sooryanarayana Varambally, Mark A Rubin, Rajal B Shah, Jindan Yu, John R Prensner, Arul M ChinnaiyanAbstract:TMPRSS2-ERG gene Fusions are the predominant molecular subtype of prostate cancer. Here, we explored the role of TMPRSS2-ERG gene Fusion Product using in vitro and in vivo model systems. Transgenic mice expressing the ERG gene Fusion Product under androgen-regulation develop mouse prostatic intraepithelial neoplasia (PIN), a precursor lesion of prostate cancer. Introduction of the ERG gene Fusion Product into primary or immortalized benign prostate epithelial cells induced an invasion-associated transcriptional program but did not increase cellular proliferation or anchorage-independent growth. These results suggest that TMPRSS2-ERG may not be sufficient for transformation in the absence of secondary molecular lesions. Transcriptional profiling of ERG knockdown in the TMPPRSS2-ERG-positive prostate cancer cell line VCaP revealed decreased expression of genes over-expressed in prostate cancer versus PIN and genes overexpressed in ETS-positive versus -negative prostate cancers in addition to inhibiting invasion. ERG knockdown in VCaP cells also induced a transcriptional program consistent with prostate differentiation. Importantly, VCaP cells and benign prostate cells overexpressing ERG directly engage components of the plasminogen activation pathway to mediate cellular invasion, potentially representing a downstream ETS target susceptible to therapeutic intervention. Our results support previous work suggesting that TMPRSS2-ERG Fusions mediate invasion, consistent with the defining histologic distinction between PIN and prostate cancer.
