This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Antonescu, C. R. Articles by Ladanyi, M. Search for Related Content PubMed PubMed Citation Articles by Antonescu, C. R. Articles by Ladanyi, M. Related Collections Commentary

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

Authors' Affiliations: Departments of ¹ Pathology and ² Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, and ³ Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts

Requests for reprints: Marc Ladanyi, Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: 212-639-6369; Fax: 212-717-3515; E-mail: ladanyim{at}mskcc.org.

Purpose: 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.

Experimental Design: 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.

Results: 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.

Conclusions: 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.

Commentary

The Impact of Genetics on Sarcoma Diagnosis: An Evolving Science

Frederic G. Barr and Paul J. Zhang
Clin. Cancer Res. 2006 12: 5256-5257. [Full Text] [PDF]

This article has been cited by other articles:

				I. Abdulkader, J. Cameselle-Teijeiro, E. de Alava, C. Ruiz-Ponte, M. M. Used-Aznar, and J. Forteza Intestinal Clear Cell Sarcoma With Melanocytic Differentiation and Extraskeletal Myxoid Chondrosarcoma Rearrangement: Report of a Case International Journal of Surgical Pathology, April 1, 2008; 16(2): 189 - 193. [Abstract] [PDF]

				A. Righi, K. Dimosthenous, and J. Rosai PEComa: Another Member of the MiT Tumor Family? International Journal of Surgical Pathology, January 1, 2008; 16(1): 16 - 20. [Abstract] [PDF]

				S. Rossi, K. Szuhai, M. Ijszenga, H. J. Tanke, L. Zanatta, R. Sciot, C. D.M. Fletcher, A. P. Dei Tos, and P. C.W. Hogendoorn EWSR1-CREB1 and EWSR1-ATF1 Fusion Genes in Angiomatoid Fibrous Histiocytoma Clin. Cancer Res., December 15, 2007; 13(24): 7322 - 7328. [Abstract] [Full Text] [PDF]

				L. Wang, R. Bhargava, T. Zheng, L. Wexler, M. H. Collins, D. Roulston, and M. Ladanyi Undifferentiated Small Round Cell Sarcomas with Rare EWS Gene Fusions: Identification of a Novel EWS-SP3 Fusion and of Additional Cases with the EWS-ETV1 and EWS-FEV Fusions J. Mol. Diagn., September 1, 2007; 9(4): 498 - 509. [Abstract] [Full Text] [PDF]