title: High prevalence of CIC fusion with double-homeobox (DUX4) transcription factors in EWSR1-negative undifferentiated small blue round cell sarcomas.
abstract: Primitive round cell sarcomas of childhood and young adults have been problematic to diagnose and classify. Our goal was to investigate the pathologic and molecular characteristics of small blue round cell tumors (SBRCT) that remained unclassified after exhaustive immunohistochemistry and molecular screening to exclude known sarcoma-related translocations. As rare examples of EWSR1-negative SBRCT have been shown to carry rearrangements for FUS and CIC genes, we undertook a systematic screening for these two genes. CIC rearrangements by FISH were detected in 15/22 (68%), while none showed FUS abnormalities. RACE, RT-PCR, and/or long-range DNA PCR performed in two cases with frozen material showed that CIC was fused to copies of the DUX4 gene on either 4q35 or 10q26.3. Subsequent FISH analysis confirmed fused signals of CIC with either 4q35 or 10q26.3 region in six cases each. Tumors positive for CIC-DUX4 fusion occurred mainly in male young adult patients (median age: 29 years), with the extremities being the most frequent location. Microscopically, tumors displayed a primitive, round to oval cell morphology with prominent nucleoli, high mitotic count, and areas of necrosis. O13 expression was variable, being either diffuse or patchy and tumors mostly lacked other markers of differentiation. Although CIC-DUX4 resulting in a t(4;19) translocation has been previously described in primitive sarcomas, this is the first report implicating the related DUX4 on 10q26 in oncogenesis. These results suggest the possibility of a newly defined subgroup of primitive round cell sarcomas characterized by CIC rearrangements, distinct from Ewing sarcoma family of tumors.
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Antoine
authors.initials: A
authors.lastname: Italiano
authors.forename: Yun Shao
authors.initials: YS
authors.lastname: Sung
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Samuel
authors.initials: S
authors.lastname: Singer
authors.forename: Robert G
authors.initials: RG
authors.lastname: Maki
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Coindre
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000627:therapeutic use; D003609:Dactinomycin / Q000008:administration & dosage / Q000627:therapeutic use; D015321:Gene Rearrangement; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D050596:Oncogene Fusion; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D034702:RNA-Binding Protein FUS / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D018228:Sarcoma, Small Cell / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D012983:Soft Tissue Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D014178:Translocation, Genetic; D014750:Vincristine / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D014408:Biomarkers, Tumor; C498610:CIC protein, human; C574694:CIC-DUX4 fusion protein, human; C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins; D015514:Oncogene Proteins, Fusion; D034702:RNA-Binding Protein FUS; D012097:Repressor Proteins; D003609:Dactinomycin; D014750:Vincristine; D003520:Cyclophosphamide
references.citation: Pediatr Dev Pathol. 2002 Nov-Dec;5(6):579-86
references.pmid: 12370769
references.citation: Am J Hum Genet. 2010 Mar 12;86(3):364-77
references.pmid: 20206332
references.citation: Hum Mol Genet. 2009 Jul 1;18(13):2414-30
references.pmid: 19359275
references.citation: Brain Res Mol Brain Res. 2002 Oct 15;106(1-2):151-6
references.pmid: 12393275
references.citation: Oncogene. 1994 May;9(5):1397-406
references.pmid: 8152800
references.citation: Mutat Res. 2008 Dec 1;647(1-2):94-102
references.pmid: 18723032
references.citation: J Neurooncol. 2005 Jun;73(2):101-8
references.pmid: 15981098
references.citation: Lancet Oncol. 2010 Feb;11(2):184-92
references.pmid: 20152770
references.citation: Genomics. 2002 Feb;79(2):210-7
references.pmid: 11829491
references.citation: Pediatr Dev Pathol. 2008 May-Jun;11(3):239-44
references.pmid: 17990934
references.citation: Hum Pathol. 2009 Nov;40(11):1600-10
references.pmid: 19647855
references.citation: Cancer Genet Cytogenet. 2009 Nov;195(1):1-11
references.pmid: 19837261
references.citation: Oncogene. 1995 Mar 16;10(6):1229-34
references.pmid: 7700648
references.citation: Cancer Genet Cytogenet. 2009 Oct;194(1):53-7
references.pmid: 19737655
references.citation: Med Pediatr Oncol. 1997 Sep;29(3):170-80
references.pmid: 9212841
references.citation: Oncologist. 2009 Oct;14(10):1013-20
references.pmid: 19808771
references.citation: Science. 2010 Sep 24;329(5999):1650-3
references.pmid: 20724583
references.citation: Genes Dev. 1992 Dec;6(12B):2502-12
references.pmid: 1340465
references.citation: Hum Mol Genet. 2006 Jul 1;15(13):2125-37
references.pmid: 16717057
references.citation: Genes Dev. 1992 Mar;6(3):481-96
references.pmid: 1547944
references.citation: Cancer Genet Cytogenet. 2010 Aug;201(1):1-5
references.pmid: 20633761
references.citation: Genes Chromosomes Cancer. 2010 Dec;49(12):1114-24
references.pmid: 20815032
references.citation: Development. 2002 Feb;129(4):993-1002
references.pmid: 11861482
references.citation: Curr Oncol Rep. 2010 Nov;12(6):402-10
references.pmid: 20820958
references.citation: PLoS Genet. 2010 Oct 28;6(10):e1001181
references.pmid: 21060811
references.citation: Cancer Genet Cytogenet. 1996 Mar;87(1):71-4
references.pmid: 8646746
references.citation: Hum Pathol. 2012 Feb;43(2):180-9
references.pmid: 21813156
references.citation: J Mol Diagn. 2007 Sep;9(4):459-63
references.pmid: 17620387
references.citation: Biochem Mol Med. 1997 Aug;61(2):127-35
references.pmid: 9259977
references.citation: Cancer Res. 2003 Aug 1;63(15):4568-76
references.pmid: 12907633
references.citation: Cancer Genet Cytogenet. 2009 Nov;195(1):12-8
references.pmid: 19837262
references.citation: Cancer Genet Cytogenet. 1992 Jun;60(2):135-40
references.pmid: 1606556