title: EWS-CREB1: a recurrent variant fusion in clear cell sarcoma--association with gastrointestinal location and absence of melanocytic differentiation.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: 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.
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.forename: Khedoudja
authors.initials: K
authors.lastname: Nafa
authors.forename: Neil H
authors.initials: NH
authors.lastname: Segal
authors.forename: Paola
authors.initials: P
authors.lastname: Dal Cin
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
mesh_terms: D051697:Activating Transcription Factor 1; D000328:Adult; D000369:Aged, 80 and over; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics; D002869:Chromosome Aberrations; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D008544:Melanocytes / Q000473:pathology*; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D034802:RNA-Binding Protein EWS / Q000235:genetics*; D000071701:Regulatory Factor X Transcription Factors; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D018227:Sarcoma, Clear Cell / Q000235:genetics* / Q000473:pathology / Q000648:ultrastructure; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000235:genetics
chemical_list: C531110:ATF1 protein, human; D051697:Activating Transcription Factor 1; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; C111598:EWS-ATF1 fusion protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D034802:RNA-Binding Protein EWS; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors