Gerald WL, Haber DA.. The EWS-WT1 gene fusion in desmoplastic small round cell tumor. Sem Cancer Biol 15: 197-205

Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Seminars in Cancer Biology (Impact Factor: 9.33). 07/2005; 15(3):197-205. DOI: 10.1016/j.semcancer.2005.01.005
Source: PubMed


Desmoplastic small round cell tumor (DSRCT) is a poorly understood neoplasm with distinctive clinical, histologic and immunophenotypic features. It is associated with a novel, specific chromosomal abnormality, t(11;22)(p13;q12) that fuses EWS with WT1 leading to production of a chimeric protein with transcriptional regulatory activity. This chimeric transcription factor has unique DNA-binding properties and regulates expression of specific target genes. Several of these have been identified and their biological role characterized. The dysregulated expression of EWS-WT1 targets contribute to the malignant phenotype of DSRCT and provide valuable insight regarding the molecular mechanisms underlying the development and progression of this distinct translocation associated tumor.

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    • "BAIAP3, this protein is believed to participate in regulated exocytosis and expressed in tumour cells of DSRCT and enhance tumour growth by secretion of autocrine or paracrine growth factors [33]. MLF1 is induced approximately eight-fold by EWSR1-WT1 (-KTS) and plays a role in proliferation and cell survival [30]. TALLA1 induction regulates interactions with extracellular matrix, migration, and invasion. "
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    ABSTRACT: Desmoplastic small round cell tumour is a rare malignant tumour with a male to female ratio of 4:1. It manifests mostly at serosal sites. Here we present a case of a 28-year-old male patient, who presented with a fast growing paratesticular mass. On biopsy nests and cords of small round cells, without a clear morphological lineage of differentiation were seen. Occasionally desmoplatic small round cell tumour shows different lines of differentiation. An unequivocal histological diagnosis might be difficult in such cases. Here we demonstrate by a combination of methods the characteristic immunohistochemical profile and - albeit unusual - molecular background and discuss the eventual link with Ewing sarcoma. Immunohistochemical studies showed a membranous staining of Keratine AE1/3 and a dot-like staining of Desmine, confirming its diagnosis. Using COBRA-FISH following a metaphase approach we demonstrated a balanced translocation, t(11;22)(p13;q12) and in RT-PCR formation of the EWSR1-WT1 fusion product, a specific translocation of desmoplastic round cell tumour. The fusion involves exon 9 of EWSR1 to exon 8 of WT1, an unusual fusion product, though earlier described in a case of a desmoplastic small round cell tumour of the hand. The EWSR1-WT1 chimera seems to function as an oncogenic transcription factor. Here the zinc finger domain of the WT1 acts with affinity with certain promoter domains influencing the expression of various downstream proteins such as: PDGFA, PAX2, insulin-like growth factor 1 receptor, epidermal growth factor receptor, IL2 receptor beta, BAIAP3, MLF1, TALLA-1, LRRC15 and ENT. We discuss their potential oncogenic roles and potential therapeutic consequences.
    01/2012; 2(1):3. DOI:10.1186/2045-3329-2-3
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    • "DSRCT is usually associated with a unique chromosomal translocation t(11;22) (p13:q12) resulting in an EWS/WT1 transcript [3, 4] which is diagnostic of this tumour [5]. This transcript codes for a protein that acts as a transcriptional activator that fails to suppress tumour growth. "
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    ABSTRACT: Desmoplastic small round cell tumour (DSRCT) is an aggressive and a rare neoplasm. We report on a 34-year-old male who had abdominal discomfort with a large intraperitoneal mass. Histological examination of the tumour biopsy revealed sheets of small round cells. The cells were positive with vimentin and desmin (with occasional dot positivity) and negative for WT1 and CD 99 with immunohistochemistry. Cytogenetics showed a translocation disrupting the EWSR 1 gene on 22 q 12 consistent with DSRCT. Electron microscopic examination showed sparse cytoplasmic organelles. The patient succumbed 34 months from disease presentation after multiple chemotherapies and thereafter radiotherapy. In summary, our case exemplifies that it is crucial to combine clinical, histological, and molecular aspects in diagnosing DSRCT especially when characteristic dot positivity with desmin is weak along with deficient marking of WT1 and CD99 by immunohistochemistry. Histology was also less clear than published examples of this entity with a poor desmoplastic response. A multidisciplinary approach including early referral to specialised centres is recommended in these cases as tertiary referral centres will be required to substantiate the diagnosis.
    Case Reports in Oncological Medicine 09/2011; 2011(6):183938. DOI:10.1155/2011/183938
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    • "The translocation fuses two specific genes: the Ewing sarcoma gene (found in Ewing's sarcoma) and the Wilms tumor 1 gene (found in Wilms' tumor), and the resultant chimera protein is thought to act as a transcriptional regulator [8]. This transcriptional factor is known to regulate the expression of specific target genes, and the dysregulated expression of the target genes is related to the invasiveness of the DSRCT [9]. Recently, connective tissue growth factor (CCN2) that is highly expressed in DSRCT, has been found to regulate the tumor cell growth, matrigenesis, and angiogenesis of this tumor [10]. "
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    ABSTRACT: Intra-abdominal desmoplastic small round cell tumor (DSRCT) is a highly malignant tumor of uncertain histogenesis. Here we report a case of DSRCT involving the stomach, initially misdiagnosed as gastric cancer. A 12-year-old boy presented with upper abdominal pain developed 1 month prior. On gastroscopy, a 7-cm mass was noted involving the esophago-gastric junction to the fundus, and positron emission tomography showed multiple hot uptakes suggesting distant metastasis. Gastroscopic biopsy showed poorly differentiated malignant cells. We diagnosed as stage IV gastric cancer and treated with 6 cycles of chemotherapy. Laparotomy revealed a huge gastric mass along with peritoneal disseminations. Palliative proximal gastrectomy was performed. Pathological examination revealed transmural involvement of DSRCT, and t(11;22)(p12;q12) was demonstrated on fluorescence in situ hybridization test. The chemotherapeutic regimen was changed and the patient underwent 8 additional cycles of post-operative chemotherapy. The patient is now alive and the residual tumor shows no significant changes after chemotherapy.
    06/2011; 80 Suppl 1(Suppl 1):S80-4. DOI:10.4174/jkss.2011.80.Suppl1.S80
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