EWS-CREB1: A Recurrent Variant Fusion in Clear Cell Sarcoma--Association with Gastrointestinal Location and Absence of Melanocytic Differentiation

Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, and Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Clinical Cancer Research (Impact Factor: 8.72). 10/2006; 12(18):5356-62. DOI: 10.1158/1078-0432.CCR-05-2811
Source: PubMed


Clear cell sarcoma (CCS) usually arises in the lower extremities of young adults and is typically associated with a t(12;22) translocation resulting in the fusion of EWS (EWSR1) with ATF1, a gene encoding a member of the cyclic AMP-responsive element binding protein (CREB) family of transcription factors. CCS arising in the gastrointestinal tract is rare and its pathologic and molecular features are not well defined.
We report a novel variant fusion of EWS to CREB1, a gene at 2q32 encoding another CREB family member highly related to ATF1, detected in three women with gastrointestinal CCS. All three cases contained an identical EWS-CREB1 fusion transcript that was shown by reverse transcription-PCR. In two of the cases tested, EWS gene rearrangement was also confirmed by fluorescence in situ hybridization and the EWS-CREB1 genomic junction fragments were isolated by long-range DNA PCR.
Morphologically, all three tumors lacked melanin pigmentation. By immunohistochemistry, there was a strong and diffuse S100 protein reactivity, whereas all melanocytic markers were negative. Ultrastructurally, two of the cases lacked melanosomes. The melanocyte-specific transcript of MITF was absent in two cases, and only weakly expressed in the third case. The Affymetrix gene expression data available in one case showed lower expression of the melanocytic genes MITF, TYR, and TYRP1, compared with four EWS-ATF1-positive CCSs of non-gastrointestinal origin.
EWS-CREB1 may define a novel subset of CCS that occurs preferentially in the gastrointestinal tract and shows little or no melanocytic differentiation. Thus, evidence of melanocytic lineage or differentiation is not a necessary feature of sarcomas with gene fusions involving CREB family members.

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    • "Tumors can also express neuroendocrine markers focally, such as chromogranin, synaptophysin, NSE, or CD56 [3, 5, 6, 13–17]. Based on this and ultrastructural findings showing lack of evidence of melanocytic differentiation but sometimes features of neural differentiation [3, 4, 6], it was proposed that CCSLGT might be redesignated as gastrointestinal neuroectodermal tumor (GNET) [17]. Most of the small numbers of CCSLGT reported have shown EWSR1-CREB1 fusions, although some harbor EWSR1-ATF1 fusions that are associated with conventional CCS. "
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    ABSTRACT: Clear cell sarcoma-like tumor of the gastrointestinal tract (CCSLGT) is a rare malignant neoplasm arising within the wall of the small bowel, stomach, or large bowel, predominantly in children and young adults. It is an aggressive tumor with a high rate of local recurrence, metastases, and early death from disease. Histologically, it is composed of relatively monomorphic ovoid or round cells with clear to eosinophilic cytoplasm, arranged in sheets and sometimes papillary or alveolar architectures, often with CD68-positive osteoclast-like giant cells in variable numbers, and is associated with EWSR1-CREB1 gene fusions. Its pathogenesis is unknown, and histologically it can be easily confused with a variety of intra-abdominal neoplasms. We describe a case of CCSLGT with molecular characterization, presenting as an acutely obstructing small bowel mass in a 33-year-old male, which occurred as a second malignant neoplasm 20 years after treatment with surgery, radiotherapy, and cisplatin and doxorubicin chemotherapy for childhood hepatoblastoma. This gives further insight into the clinical setting of this highly aggressive neoplasm and highlights the use of radiation therapy as a possible etiologic factor.
    Full-text · Article · Feb 2014 · Case Reports in Medicine
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    • "EWS is able to form a fusion transcript with CREB1 in several soft tissue tumors. It was also described as a recurrent variant fusion in clear-cell sarcomas [65, 66] and in angiomatoid fibrous histiocytoma [67]. More recently, a EWS–CREB1 translocation has been described in a case of small blue round cell tumor of the interosseous membrane [68]. "
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    ABSTRACT: Soft tissue tumors are a heterogeneous group of tumors, traditionally classified according to morphology and histogenesis. Molecular classification divides sarcomas into two main categories: (a) sarcomas with specific genetic alterations and (b) sarcomas showing multiple complex karyotypic abnormalities without any specific pattern. Most chromosomal alterations are represented by translocations which are increasingly detected. The identification of fusion transcripts, in fact, not only support the diagnosis but also provides the basis for the development of new therapeutic strategies aimed at blocking aberrant activity of the chimeric proteins. One of the genes most susceptible to breakage/translocation in soft tissue tumors is represented by Ewing sarcoma breakpoint region 1 (EWSR1). This gene has a large number of fusion partners, mainly associated with the pathogenesis of Ewing's sarcoma but with other soft tissue tumors too. In this review, we illustrate the characteristics of this gene/protein, both in normal cellular physiology and in carcinogenesis. We describe the different fusion partners of EWSR1, the molecular pathways in which is involved and the main molecular biology techniques for the identification of fusion transcripts and for their inhibition.
    Full-text · Article · Mar 2013 · Medical Oncology
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    • "They have abundant clear or eosinophilic cytoplasm and vesicular nuclei with prominent nucleoli. However, the majority of cases of CCS of the soft parts are characterized by expression of melanocytic markers (HMB45, A103, MITF and so on) more often than gastrointestinal CCS, where most tumors are negative for these markers [4]. In addition, a histologic variant of gastrointestinal CCS has been described, where the presence of scattered osteoclast-like multinucleated giant cells is the dominant feature [9]. "
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    ABSTRACT: Background Clear cell sarcoma (CCS), also known as malignant melanoma of soft parts, is a rare type of soft tissue sarcoma which exhibits morphological, immunohistochemical and ultrastructural similarity with malignant melanoma. It is rarely localized in the intestine and the natural history of this tumor is not yet clear. Case report A 49-year-old woman presented with diffuse abdominal colicky pain and vomitus over the previous seven days. An X-ray of the abdomen revealed obstruction of the small intestine. The patient underwent contrast enhanced abdominal computerized tomography (CT), which confirmed the obstruction at the jejunum and an associated circumferential wall thickening extending about 3 cm in length, causing concentric narrowing of the lumen. At laparotomy, a mass was recognized at the level of the jejunum in the small intestine, which caused almost complete obstruction of the lumen. At the point of obstruction, adhered loops of small intestine were found. A segmental small bowel resection was performed with 5 cm clear margins and its respective mesenteric lymph nodes. Results Histological examination of the specimen revealed a tumor (3×3×2cm) with epithelioid cell characteristics and eosinophilic or clear cytoplasm and focal translucent nuclei. Immunohistochemistry was positive for S100, epithelial membrane antigen (EMA) and synaptophysin. The tumor was pankeratin AE1/AE2, GFAP, HMB45 and MART-1/Melan-A negative. Twelve lymph nodes were retrieved and were free of neoplastic infiltration. Cytogenetic examination revealed translocation of the EWSR1 gene. The patient had an uncomplicated postoperative course and left the hospital seven days after her admission in good general condition. After 20 months of follow-up the patient remains asymptomatic without any clinical or radiological evidence of recurrence. Conclusion CCS sarcoma can be rarely localized in the jejunum. Due to its morphological similarity to malignant melanoma, cytogenetic examination is necessary for its diagnosis. Wide resection of the tumor and its respective lymph nodes was associated with a 20-month disease free survival in this patient.
    Full-text · Article · Jan 2013 · World Journal of Surgical Oncology
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