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Detailed cytogenetic and array analysis of pediatric primitive sarcomas reveals a recurrent CIC–DUX4 fusion gene event

  • Maisa Yoshimoto
    Affiliations
    Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada
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  • Cassandra Graham
    Affiliations
    Department of Paediatric Laboratory Medicine, Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada

    Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
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  • Susan Chilton-MacNeill
    Affiliations
    Department of Paediatric Laboratory Medicine, Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada
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  • Eric Lee
    Affiliations
    Department of Paediatric Laboratory Medicine, Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada
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  • Mary Shago
    Affiliations
    Department of Paediatric Laboratory Medicine, Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada

    Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
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  • Jeremy Squire
    Affiliations
    Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada
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  • Maria Zielenska
    Affiliations
    Department of Paediatric Laboratory Medicine, Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada

    Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
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  • Gino R. Somers
    Correspondence
    Corresponding author. Tel.: (416) 813-6848; fax: (416) 813-5974.
    Affiliations
    Department of Paediatric Laboratory Medicine, Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada

    Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
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      Abstract

      Pediatric undifferentiated soft tissue sarcomas (USTS) are a diagnostically challenging group of neoplasms. Recently, a subcategory of USTS with primitive round cell morphology and a t(4;19)(q35;q13) rearrangement has been defined. The present study applied high-throughput array comparative genomic hybridization together with spectral karyotyping, four-color fluorescence in situ hybridization (FISH), and reverse transcriptase–polymerase chain reaction (RT-PCR) to a series of three pediatric USTS. Two of these had primitive round cell morphology with CD99 positivity; the third had a spindled and myxoid appearance. By genomic analyses, both primitive round cell sarcomas had t(4;19)(q13;q35) rearrangements in addition to several imbalances throughout the genome. Four-color FISH and in silico analyses of the breakpoint region at 19q13 identified the potential involvement of the candidate oncogene CIC. By RT-PCR, fusion transcripts involving CIC (19q13) and DUX4 (4q35) were confirmed to be present in both primitive round cell sarcomas, further defining the breakpoints seen by genomic analysis. Described here are two tumors belonging to the rare category of CIC–DUX4-positive primitive sarcomas, with detailed cytogenetic and genomic information regarding this novel subclass of pediatric malignancy. Molecular and cytogenetic techniques for the detection of the CIC–DUX4 fusion gene are described, to aid in recognition and diagnosis.
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      References

        • Mackall C.L.
        • Meltzer P.S.
        • Helman L.J.
        Focus on sarcomas.
        Cancer Cell. 2002; 2: 175-178
        • Meyer W.H.
        • Spunt S.L.
        Soft tissue sarcomas of childhood.
        Cancer Treat Rev. 2004; 30: 269-280
        • Coffin C.M.
        • Dehner L.P.
        • O'Shea P.A.
        Pediatric soft tissue tumors: a clinical, pathological, and therapeutic approach.
        Williams & Wilkins, Baltimore, MD1997
        • Helman L.J.
        • Meltzer P.
        Mechanisms of sarcoma development.
        Nat Rev Cancer. 2003; 3: 685-694
      1. Fletcher C.D.M. Unni K.K. Mertens F. Pathology and genetics of tumours of soft tissue and bone. World Health Organization Classification of Tumours. IARC Press, Lyon2002
        • Sorensen P.H.
        • Lessnick S.L.
        • Lopez-Terrada D.
        • Liu X.F.
        • Triche T.J.
        • Denny C.T.
        A second Ewing's sarcoma translocation, t(21;22), fuses the EWS gene to another ETS-family transcription factor, ERG.
        Nat Genet. 1994; 6: 146-151
        • Dei Tos A.P.
        • Maestro R.
        • Doglioni C.
        • Piccinin S.
        • Libera D.D.
        • Boiocchi M.
        • Fletcher C.D.
        Tumor suppressor genes and related molecules in leiomyosarcoma.
        Am J Pathol. 1996; 148: 1037-1045
        • Qualman S.J.
        • Coffin C.M.
        • Newton W.A.
        • Hojo H.
        • Triche T.J.
        • Parham D.M.
        • Crist W.M.
        Intergroup Rhabdomyosarcoma Study: update for pathologists.
        Pediatr Dev Pathol. 1998; 1: 550-561
        • Sebire N.J.
        • Ramsay A.D.
        • Levitt G.
        • Malone M.
        • Risdon R.A.
        Aberrant immunohistochemical expression in nonrhabdomyosarcoma soft tissue sarcomas of infancy: retrospective review of clinical material.
        Pediatr Dev Pathol. 2002; 5: 579-586
        • Gonzalez-Crussi F.
        • Black-Schaffer S.
        Rhabdomyosarcoma of infancy and childhood: problems of morphologic classification.
        Am J Surg Pathol. 1979; 3: 157-171
        • Somers G.R.
        • Gupta A.A.
        • Doria A.S.
        • Ho M.
        • Pereira C.
        • Shago M.
        • Thorner P.
        • Zielenska M.
        Pediatric undifferentiated sarcoma of the soft tissues: a clinicopathologic study.
        Pediatr Dev Pathol. 2006; 9: 132-142
        • Selvarajah S.
        • Yoshimoto M.
        • Prasad M.
        • Shago M.
        • Squire J.
        • Zielenska M.
        • Somers G.R.
        Characterization of trisomy 8 in pediatric undifferentiated sarcomas using advanced molecular cytogenetic techniques.
        Cancer Genet Cytogenet. 2007; 174: 35-41
        • Richkind K.E.
        • Romansky S.G.
        • Finklestein J.Z.
        t(4;19)(q35;q13.1): a recurrent change in primitive mesenchymal tumors?.
        Cancer Genet Cytogenet. 1996; 87: 71-74
        • Kawamura-Saito M.
        • Yamazaki Y.
        • Kaneko K.
        • Kawaguchi N.
        • Kanda H.
        • Mukai H.
        • Gotoh T.
        • Motoi T.
        • Fukayama M.
        • Aburatani H.
        • Takizawa T.
        • Nakamura T.
        Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation.
        Hum Mol Genet. 2006; 15: 2125-2137
        • Rakheja D.
        • Goldman S.
        • Wilson K.S.
        • Lenarsky C.
        • Weinthal J.
        • Schultz R.A.
        Translocation (4;19)(q35;q13.1)-associated primitive round cell sarcoma: report of a case and review of the literature.
        Pediatr Dev Pathol. 2008; 11: 239-244
        • Somers G.R.
        • Shago M.
        • Zielenska M.
        • Chan H.S.
        • Ngan B.Y.
        Primary subcutaneous primitive neuroectodermal tumor with aggressive behavior and an unusual karyotype: case report.
        Pediatr Dev Pathol. 2004; 7: 538-545
        • Bayani J.
        • Zielenska M.
        • Pandita A.
        • Al-Romaih K.
        • Karaskova J.
        • Harrison K.
        • Bridge J.A.
        • Sorensen P.
        • Thorner P.
        • Squire J.A.
        Spectral karyotyping identifies recurrent complex rearrangements of chromosomes 8, 17, and 20 in osteosarcomas.
        Genes Chromosomes Cancer. 2003; 36: 7-16
        • Ausubel F.M.
        • Brent R.
        • Kingston R.E.
        • Moore D.D.
        • Seidman J.G.
        • Smith J.A.
        • Sturhl K.
        Short protocols in molecular biology.
        5th ed. John Wiley, New York2002
        • Yoshimoto M.
        • Joshua A.M.
        • Cunha I.W.
        • Coudry R.A.
        • Fonseca F.P.
        • Ludkovski O.
        • Zielenska M.
        • Soares F.A.
        • Squire J.A.
        Absence of TMPRSS2:ERG fusions and PTEN losses in prostate cancer is associated with a favorable outcome.
        Mod Pathol. 2008; 21: 1451-1460
        • Wang L.
        • Bhargava R.
        • Zheng T.
        • Wexler L.
        • Collins M.H.
        • Roulston D.
        • Ladanyi M.
        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. 2007; 9: 498-509
        • Mathas S.
        • Kreher S.
        • Meaburn K.J.
        • Jöhrens K.
        • Lamprecht B.
        • Assaf C.
        • Sterry W.
        • Kadin M.E.
        • Daibata M.
        • Joos S.
        • Hummel M.
        • Stein H.
        • Janz M.
        • Anagnostopoulos I.
        • Schrock E.
        • Misteli T.
        • Dörken B.
        Gene deregulation and spatial genome reorganization near breakpoints prior to formation of translocations in anaplastic large cell lymphoma.
        Proc Natl Acad Sci U S A. 2009; 106: 5831-5836
        • Lee C.J.
        • Chan W.I.
        • Cheung M.
        • Cheng Y.C.
        • Appleby V.J.
        • Orme A.T.
        • Scotting P.J.
        CIC, a member of a novel subfamily of the HMG-box superfamily, is transiently expressed in developing granule neurons.
        Brain Res Mol Brain Res. 2002; 106: 151-156
        • Lee C.J.
        • Chan W.I.
        • Scotting P.J.
        CIC, a gene involved in cerebellar development and ErbB signaling, is significantly expressed in medulloblastomas.
        J Neurooncol. 2005; 73: 101-108
        • Gabriëls J.
        • Beckers M.C.
        • Ding H.
        • De Vriese A.
        • Plaisance S.
        • van der Maarel S.M.
        • Padberg G.W.
        • Frants R.R.
        • Hewitt J.E.
        • Collen D.
        • Belayew A.
        Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element.
        Gene. 1999; 236: 25-32
        • Dixit M.
        • Ansseau E.
        • Tassin A.
        • Winokur S.
        • Shi R.
        • Qian H.
        • Sauvage S.
        • Mattéotti C.
        • van Acker A.M.
        • Leo O.
        Figlew DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1.
        Proc Natl Acad Sci U S A. 2007; 104: 18157-18162
        • Kowaljow V.
        • Marcowycz A.
        • Ansseau E.
        • Conde C.B.
        • Sauvage S.
        • Mattéotti C.
        • Arias C.
        • Corona E.D.
        • Nuñez N.G.
        • Leo O.
        • Wattiez R.
        • Figlewicz D.
        • Laoudj-Chenivesse D.
        • Belayew A.
        • Coppée F.
        • Rosa A.L.
        The DUX4 gene at the FSHD1A locus encodes a pro-apoptotic protein.
        Neuromuscul Disord. 2007; 17: 611-623

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        Cancer Genetics and CytogeneticsVol. 197Issue 1
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          Yoshimoto M, Graham C, Chilton-MacNeill S, Lee E, Shago M, Squire J, Zielenska M, Somers GR. Detailed cytogenetic and array analysis of pediatric primitive sarcomas reveals a recurrent CIC—DUX4 fusion gene event. Cancer Genet Cytogenet 2009;195:1-11.
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