A novel t(4;22)(q31;q12) produces an EWSR1-SMARCA5 fusion in extraskeletal Ewing sarcoma/primitive neuroectodermal tumor. Mod Pathol

Division of Bone Marrow Transplantation and Immunodeficiency, Cincinnati Childern's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
Modern Pathology (Impact Factor: 6.19). 11/2010; 24(3):333-42. DOI: 10.1038/modpathol.2010.201
Source: PubMed


Over 90% of Ewing sarcoma/primitive neuroectodermal tumors (PNETs) feature an 11;22 translocation leading to an EWSR1-FLI1 fusion. Less commonly, a member of the ETS-transcription factor family other than FLI1 is fused with EWSR1. In this study, cytogenetic analysis of an extraskeletal Ewing sarcoma/PNET revealed a novel chromosomal translocation t(4;22)(q31;q12) as the sole anomaly. Following confirmation of an EWSR1 rearrangement by the use of EWSR1 breakpoint flanking probes, a fluorescence in situ hybridization positional cloning strategy was used to further narrow the 4q31 breakpoint. These analyses identified the breakpoint within RP11-481K16, a bacterial artificial chromosome (BAC) clone containing two gene candidates FREM and SMARCA5. Subsequent RACE, RT-PCR, and sequencing studies were conducted to further characterize the fusion transcript. An in-frame fusion of the first 7 exons of EWSR1 to the last 19 exons of SMARCA5 was identified. SMARCA5 encodes for hSNF2H, a chromatin-remodeling protein. Analogous to EWSR1-ETS-expressing NIH3T3 cells, NIH3T3 cells expressing EWSR1-hSNF2H exhibited anchorage-independent growth and formed colonies in soft agar, indicating chimeric protein tumorigenic potential. Conversely, expression of EWSR1-hSNF2H in NIH3T3 cells, unlike EWSR1-ETS fusions, did not induce EAT-2 expression. Mapping analysis demonstrated that deletion of the C-terminus (SLIDE or SANT motives) of hSNF2H impaired, and deletion of the SNF2_N domain fully abrogated NIH3T3 cell transformation by EWSR1-SMARCA5. It is proposed that EWSR1-hSNF2H may act as an oncogenic chromatin-remodeling factor and that its expression contributes to Ewing sarcoma/primitive neuroectodermal tumorigenesis. To the best of our knowledge, this is the first description of a fusion between EWSR1 and a chromatin-reorganizing gene in Ewing sarcoma/PNET and thus expands the EWSR1 functional partnership beyond transcription factor and zinc-finger gene families.

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Available from: Marilu Nelson, May 08, 2014
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    • "Cytogenetic abnormalities are highly specific to ETs; chromosome 22 is most frequently involved in structural changes detected in cells of ES. Although t(11;22) is most frequent, chromosome 22 is also involved in other translocations in neoplasia, suggesting that the break point on chromosome 22 seen in ES cells may be a more important factor in the origin of this tumor than the loci to which the deleted segment is translocated.[156121314] In a case of ES which Whang-Peng et al.[15] examined it had a translocation involving chromosome 6 and 12, with a break point (12p13).[15] "
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    ABSTRACT: Cytogenetic or immunohistochemical studies are often required to differentiate Ewing's sarcoma (ES) from other small round cell tumors. Herein we report a case of 13-year-old boy who presented with a large presacral lesion. Hemogram and biochemical parameters were normal except lactate dehydrogenase showing value of 96.40/IU/L, magnetic resonance imaging of the spine showed a large mass in presacral lesion (8 cm × 7 cm × 9 cm), with destruction of the sacrum (S2 S3 and S4) with interspinal extension. Bone scan showed multiple pelvic bone lesions, radiograph of chest, ultrasound of abdomen, pelvis and electrocardiogram were within normal limits. Bone marrow was not involved. Cells from the fine needle aspirate were cultured for short term using RPMI medium and karyotype obtained showed a t(12;22)(p12;q12) instead of the classic t(11;22). Diagnosis of ES was also confirmed by studies using immunohistochemistry for MIC2 which was positive, synaptophysin was inconclusive and leukocyte common antigen, desmin negative. This case provides evidence of the importance of chromosome 22, in the etiology of the disease.
    Full-text · Article · Apr 2014 · Indian journal of medical and paediatric oncology
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    • "More recently the possibility of SMARCA5 to produce a fusion transcript in extraskeletal Ewing sarcoma/primitive neuroectodermal tumor has been described. The breakpoint involved EWS exon 7 and SMARCA5 exon 8 [80]. "
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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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    • "In this case, the EWSR1 gene is fused to the chromatinremodelling gene SMARCA5. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes (Sumegi et al, 2010). "

    Full-text · Article · Jun 2012 · EMBO Molecular Medicine
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