Recurrent EWSR1-CREB3L1 gene fusions in sclerosing epithelioid fibrosarcoma.
Sclerosing epithelioid fibrosarcoma (SEF) and low-grade fibromyxoid sarcoma (LGFMS) are 2 distinct types of sarcoma, with a subset of cases showing overlapping morphologic and immunohistochemical features. LGFMS is characterized by expression of the MUC4 protein, and about 90% of cases display a distinctive FUS-CREB3L2 gene fusion. In addition, SEF is often MUC4 positive, but is genetically less well studied. Fluorescence in situ hybridization (FISH) studies have shown involvement of the FUS gene in the majority of so-called hybrid LGFMS/SEF and in 10% to 25% of sarcomas with pure SEF morphology. In this study, we investigated a series of 10 primary tumors showing pure SEF morphology, 4 cases of LGFMS that at local or distant relapse showed predominant SEF morphology, and 1 primary hybrid LGFMS/SEF. All but 1 case showed diffuse expression for MUC4. Using FISH, reverse transcription polymerase chain reaction, and/or mRNA sequencing in selected cases, we found recurrent EWSR1-CREB3L1 fusion transcripts by reverse transcription polymerase chain reaction in 3/10 pure SEF cases and splits and deletions of the EWSR1 and/or CREB3L1 genes by FISH in 6 additional cases. All 5 cases of LGFMS with progression to SEF morphology or hybrid features had FUS-CREB3L2 fusion transcripts. Our results indicate that EWSR1 and CREB3L1 rearrangements are predominant over FUS and CREB3L2 rearrangements in pure SEF, highlighting that SEF and LGFMS are different tumor types, with different impacts on patient outcome.
*Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, Lund, Sweden †Department of Musculoskeletal Pathology and Orthopaedic Oncology, Royal Orthopaedic Hospital NHS Foundation Trust and Division of Cancer Studies, Medical School, University of Birmingham, Birmingham ‡Department of Histopathology, Royal Marsden Hospital, London, UK.
Elsa
E
Arbajian
Florian
F
Puls
Linda
L
Magnusson
Khin
K
Thway
Cyril
C
Fisher
Vaiyapuri P
VP
Sumathi
Johnbosco
J
Tayebwa
Karolin H
KH
Nord
Lars-Gunnar
LG
Kindblom
Fredrik
F
Mertens
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics*; D015622:Epithelioid Cells / Q000737:chemistry / Q000473:pathology; D005260:Female; D005350:Fibroma / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D005354:Fibrosarcoma / Q000737:chemistry / Q000235:genetics* / Q000556:secondary; D050939:Gene Fusion; D015321:Gene Rearrangement; D020022:Genetic Predisposition to Disease; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D055264:Mucin-4 / Q000032:analysis; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D034802:RNA-Binding Protein EWS; D034702:RNA-Binding Protein FUS / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012598:Sclerosis; D017423:Sequence Analysis, RNA; D012983:Soft Tissue Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
D014408:Biomarkers, Tumor; C485618:CREB3L1 protein, human; D002148:Calmodulin-Binding Proteins; D017362:Cyclic AMP Response Element-Binding Protein; C500986:EWSR1 protein, human; C524658:MUC4 protein, human; D055264:Mucin-4; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D034802:RNA-Binding Protein EWS; D034702:RNA-Binding Protein FUS; D016601:RNA-Binding Proteins