title: CIC-DUX sarcomas demonstrate frequent MYC amplification and ETS-family transcription factor expression.
abstract: Recent molecular advances have identified a novel, clinically aggressive subgroup of undifferentiated round cell sarcomas defined molecularly by oncogenic fusion of the gene, CIC, and either DUX4 or its paralog, DUX4L, herein termed CIC-DUX sarcomas. Morphologically, CIC-DUX sarcomas are round cell sarcomas with high-grade nuclear features, including vesicular chromatin and nucleoli, patchy clear cell foci, myxoid change, and necrosis. Here, we studied a cohort of 10 cases, including 6 newly identified cases, 2 with paired metastases. Given our prior observation of trisomy 8 in these tumors, we assayed for amplification and expression of MYC (c-Myc) and representative downstream targets. Trisomy 8 was detected in 5/7 testable cases, with further amplification of MYC locus in 6/7 testable cases and immunohistochemical expression of MYC in 10/10. The canonical MYC transcriptional target, p21, but not MTDH, was differentially expressed compared with Ewing sarcomas. Given prior observation of induction of ETS-family transcription factors by the fusion oncoprotein, we assayed and identified highly prevalent positivity for ERG (9/10) and FLI1 (8/8). These findings are cautionary regarding use of these immunostains in prospective case workup, whereas the prevalent MYC amplification may represent a therapeutically targetable oncogenic pathway in CIC-DUX sarcomas.
authors.affiliation: 1] Department of Pathology, University of Michigan Health System, Ann Arbor, MI, USA [2] Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Steven Christopher
authors.initials: SC
authors.lastname: Smith
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin Hospital, Madison, WI, USA.
authors.forename: Darya
authors.initials: D
authors.lastname: Buehler
authors.affiliation: Department of Pathology, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Eun-Young Karen
authors.initials: EY
authors.lastname: Choi
authors.affiliation: Department of Pathology, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: McHugh
authors.affiliation: Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Rubin
authors.affiliation: Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Billings
authors.affiliation: Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Balzer
authors.affiliation: Department of Pathology, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Dafydd G
authors.initials: DG
authors.lastname: Thomas
authors.affiliation: Department of Pathology, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Lucas
authors.affiliation: Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Goldblum
authors.affiliation: 1] Department of Pathology, University of Michigan Health System, Ann Arbor, MI, USA [2] Department of Dermatology, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Rajiv M
authors.initials: RM
authors.lastname: Patel
mesh_terms: D000328:Adult; D005260:Female; D005784:Gene Amplification; D016259:Genes, myc / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D015514:Oncogene Proteins, Fusion; D016133:Polymerase Chain Reaction; D050783:Proto-Oncogene Proteins c-ets / Q000096:biosynthesis*; D012097:Repressor Proteins / Q000235:genetics; D012189:Retrospective Studies; D018228:Sarcoma, Small Cell / Q000235:genetics* / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
chemical_list: C498610:CIC protein, human; C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins; D015514:Oncogene Proteins, Fusion; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins