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A novel t(4;22)(q31;q12) produces an EWSR1-SMARCA5 fusion in extraskeletal Ewing sarcoma/primitive neuroectodermal tumor.
Mod Pathol. 2011 Mar; 24(3):333-42.MP

Abstract

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.

Authors+Show Affiliations

Division of Bone Marrow Transplantation and Immunodeficiency, Cincinnati Childern's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21113140

Citation

Sumegi, Janos, et al. "A Novel T(4;22)(q31;q12) Produces an EWSR1-SMARCA5 Fusion in Extraskeletal Ewing Sarcoma/primitive Neuroectodermal Tumor." Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc, vol. 24, no. 3, 2011, pp. 333-42.
Sumegi J, Nishio J, Nelson M, et al. A novel t(4;22)(q31;q12) produces an EWSR1-SMARCA5 fusion in extraskeletal Ewing sarcoma/primitive neuroectodermal tumor. Mod Pathol. 2011;24(3):333-42.
Sumegi, J., Nishio, J., Nelson, M., Frayer, R. W., Perry, D., & Bridge, J. A. (2011). A novel t(4;22)(q31;q12) produces an EWSR1-SMARCA5 fusion in extraskeletal Ewing sarcoma/primitive neuroectodermal tumor. Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc, 24(3), 333-42. https://doi.org/10.1038/modpathol.2010.201
Sumegi J, et al. A Novel T(4;22)(q31;q12) Produces an EWSR1-SMARCA5 Fusion in Extraskeletal Ewing Sarcoma/primitive Neuroectodermal Tumor. Mod Pathol. 2011;24(3):333-42. PubMed PMID: 21113140.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel t(4;22)(q31;q12) produces an EWSR1-SMARCA5 fusion in extraskeletal Ewing sarcoma/primitive neuroectodermal tumor. AU - Sumegi,Janos, AU - Nishio,Jun, AU - Nelson,Marilu, AU - Frayer,Robert W, AU - Perry,Deborah, AU - Bridge,Julia A, Y1 - 2010/11/26/ PY - 2010/11/30/entrez PY - 2010/11/30/pubmed PY - 2011/6/10/medline SP - 333 EP - 42 JF - Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc JO - Mod Pathol VL - 24 IS - 3 N2 - 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. SN - 1530-0285 UR - https://www.unboundmedicine.com/medline/citation/21113140/A_novel_t_4/primitive_neuroectodermal_tumor_ L2 - https://doi.org/10.1038/modpathol.2010.201 DB - PRIME DP - Unbound Medicine ER -