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

Italiano, A., Sung, Y. S., Zhang, L., Singer, S., Maki, R. G., Coindre, J. M., Antonescu, C. R. (March 2012) High prevalence of CIC fusion with double-homeobox (DUX4) transcription factors in EWSR1-negative undifferentiated small blue round cell sarcomas. Genes Chromosomes Cancer, 51 (3). pp. 207-18. ISSN 1098-2264 (Electronic)1045-2257 (Linking)

URL: https://www.ncbi.nlm.nih.gov/pubmed/22072439
DOI: 10.1002/gcc.20945

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.

Item Type: Paper
Uncontrolled Keywords: Adolescent Adult Aged Antineoplastic Combined Chemotherapy Protocols/administration & dosage/therapeutic use Base Sequence Biomarkers, Tumor/genetics Chromosomes, Human, Pair 10/genetics Chromosomes, Human, Pair 4/genetics Cyclophosphamide/administration & dosage/therapeutic use Dactinomycin/administration & dosage/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/drug therapy/*genetics Soft Tissue Neoplasms/diagnosis/drug therapy/*genetics Translocation, Genetic Vincristine/administration & dosage/therapeutic use
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > chromosome
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > chromosomes, structure and function > chromosome

bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > homeodomain protein
diseases & disorders > cancer > cancer types > sarcoma
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor
CSHL Authors:
Communities: CSHL labs > Maki lab
Depositing User: Matt Covey
Date: March 2012
Date Deposited: 21 Oct 2016 15:05
Last Modified: 21 Oct 2016 15:05
PMCID: PMC3404826
Related URLs:
URI: http://repository.cshl.edu/id/eprint/33736

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