High prevalence of CIC fusion with double-homeobox (DUX4) transcription factors in EWSR1-negative undifferentiated small blue round cell sarcomas

Genes Chromosomes Cancer. 2012 Mar;51(3):207-18. doi: 10.1002/gcc.20945. Epub 2011 Nov 10.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Base Sequence
  • Biomarkers, Tumor / genetics
  • Chromosomes, Human, Pair 10 / genetics
  • Chromosomes, Human, Pair 4 / genetics
  • Cyclophosphamide / administration & dosage
  • Cyclophosphamide / therapeutic use
  • Dactinomycin / administration & dosage
  • Dactinomycin / therapeutic use
  • Gene Rearrangement
  • Homeodomain Proteins / genetics*
  • Humans
  • In Situ Hybridization, Fluorescence
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Oncogene Fusion*
  • Oncogene Proteins, Fusion / genetics*
  • RNA-Binding Protein FUS / genetics
  • Repressor Proteins / genetics*
  • Sarcoma, Small Cell / diagnosis
  • Sarcoma, Small Cell / drug therapy
  • Sarcoma, Small Cell / genetics*
  • Soft Tissue Neoplasms / diagnosis
  • Soft Tissue Neoplasms / drug therapy
  • Soft Tissue Neoplasms / genetics*
  • Translocation, Genetic
  • Vincristine / administration & dosage
  • Vincristine / therapeutic use


  • Biomarkers, Tumor
  • CIC protein, human
  • CIC-DUX4 fusion protein, human
  • DUX4L1 protein, human
  • Homeodomain Proteins
  • Oncogene Proteins, Fusion
  • RNA-Binding Protein FUS
  • Repressor Proteins
  • Dactinomycin
  • Vincristine
  • Cyclophosphamide

Supplementary concepts

  • VAC protocol