Soft Tissues: Pediatric undifferentiated sarcoma with t(4;19)(q35;q13)

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Soft Tissues: Pediatric undifferentiated sarcoma with t(4;19)(q35;q13)

Written	2011-11	Cassandra Graham, Gino Somers
		Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, M5G 1X8, ON, Canada

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Identity

ICD-Topo C470-C476,C478-C479,C490-C496,C498-C499 CONNECTIVE & SOFT TISSUE

ICD-Morpho 9364/3 9260/3 Peripheral neuroectodermal tumor

Atlas_Id 5714

Phylum Soft Tissues::Pediatric undifferentiated soft tissue sarcoma
WHO/OMS Classification Soft Tissues

Other names CIC-DUX4-positive pediatric primitive round cell sarcomas
Ewing-like sarcomas with t(4;19)(q25;q13) translocation
CIC fusion with DUX4 in EWSR1-negative undifferentiated small blue round cell sarcomas
t(4;19)(q35;13.1) in primitive mesenchymal tumors
Translocation (4;19)(q35;q13.1)-associated primitive round cell sarcomas

Clinics and Pathology

Disease Approximately 5% of sarcomas remain unclassifiable using current diagnostic techniques. These tumors, termed undifferentiated soft tissue sarcomas, show no specific lineage differentiation and exhibit no well established immunohistochemical profile (Somers et al., 2006). Recently, a subclass of undifferentiated sarcomas with primitive round cell morphology were found to harbor a CIC-DUX4 fusion gene resulting from a t(4;19)(q35;q13) rearrangement.

Epidemiology A total of 8 pediatric cases have been reported to date (Richkind et al., 1996; Rakheja et al., 2008; Yoshimoto et al., 2009; Graham et al., 2011; Italiano et al., 2011). There seems to be no sex predilection as 4 patients were male and 4 patients were female. Tumors occurred in children with a median age of 11.5 years (range 6-16), with no difference between the ages of the males and females.

Clinics Primary tumors were located in the trunk (n=4), lower extremities (n=3) and head and neck (n=1). Of the 8 patients, 3 patients died as a result of the disease and 5 were alive at last stated follow-up.

Pathology Tumors are composed of primitive round cells arranged in sheets or nests, with increased nuclear:cytoplasmic ratios. No evidence of differentiation is discernible at the light microscopy level. The majority are positive for CD99 in either a membranous or cytoplasmic pattern of expression.

Photomicrograph of a primitive round cell sarcoma harbouring a CIC-DUX4 fusion transcript.

Genetics

Note This fusion gene has been identified using various molecular genetic and cytogenetic methods including real-time polymerase chain reaction (RT-PCR), G-banding, Spectral Karyotyping (SKY) and Fluorescence in situ hybridization (FISH).

Cytogenetics

Note This fusion gene cannot always be detected using gross cytogenetic techniques (G-banding/SKY). In at least one case, SKY did not identify the fusion gene, but subsequent FISH and RT-PCR analyses found the case to be positive for the t(4;19)(q35;q13) (Yoshimoto et al., 2009).

Cytogenetics Molecular Fluorescence in situ hybridization (FISH) with probes for the CIC and DUX4 genes can be used to detect the CIC-DUX4 rearrangement, as it displays fusion of signals on one chromosome.

Genes involved and Proteins

Gene Name CIC (capicua transcriptional repressor)

Location 19q13.2

Protein The human CIC gene is an ortholog of the Drosophila capicua gene, and is a member of the HMG-box superfamily of transcription factors (Lee et al., 2002). This gene has 20 exons encoding a protein of 1608 amino acids, and contains an N-terminal DNA-binding HMG-box and sixteen possible MAPK phosphorylation sites. CIC has been shown to be involved in mediating two oncogenic signalling pathways, EGFR and Wnt, by transcriptional repression (Lee et al., 2005).

Gene Name DUX4 (double homeobox 4)

Location 4q35.2

Protein The DUX4 gene is a double-homeobox gene belonging to the family of double homeodomain transcriptional activators. DUX4 is located within the tandem repeat locus D4Z4 on chromosome 4 and contains two DNA-binding homeoboxes at its N-terminus (Gabriels et al., 1999). A similar D4Z4 repeat has been identified on chromosome 10.

Result of the chromosomal anomaly

Hybrid Gene
Description 5' CIC - 3' DUX4. Fusion of exon 20 of the CIC gene and exon 1 of the DUX4 gene, resulting in an in-frame fusion between CIC and DUX4 with the CIC open reading frame and the DUX4 stop codon. In 5 of the 8 cases the fusion breakpoint was mapped, and 4 distinct breakpoints within exon 20 of CIC and exon 1 of DUX4 were identified (Yoshimoto et al., 2009; Graham et al., 2011).

Fusion Protein
Note Protein prediction suggests that this fusion leaves intact the majority of the CIC protein functional domains, including the DNA-binding high-mobility group (HMG)-box, and 15 of 16 putative MAPK phosphorylation sites, but results in the loss of the majority of the DUX4 protein functional domains, namely both DNA-binding homeodomains (Graham et al., 2011).

To be noted

An additional 7 adult cases of t(4;19)(q35;q13)-positive undifferentiated soft tissue sarcomas have been reported to date (Kawamura-Saito et al., 2006; Italiano et al., 2011). Furthermore, 6 cases (1 pediatric and 5 adult) have been identified which harbor a fusion between the CIC gene on chromosome 19 and the DUX10 gene (DUX4 homolog) on chromosome 10 (Italiano et al., 2011).

Bibliography

Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element.

Gabriels J, Beckers MC, Ding H, De Vriese A, Plaisance S, van der Maarel SM, Padberg GW, Frants RR, Hewitt JE, Collen D, Belayew A.

Gene. 1999 Aug 5;236(1):25-32.

PMID 10433963

The CIC-DUX4 fusion transcript is present in a subgroup of pediatric primitive round cell sarcomas.

Graham C, Chilton-Macneill S, Zielenska M, Somers GR.

Hum Pathol. 2011 Aug 1. [Epub ahead of print]

PMID 21813156

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

Italiano A, Sung YS, Zhang L, Singer S, Maki RG, Coindre JM, Antonescu CR.

Genes Chromosomes Cancer. 2011 Nov 10. doi: 10.1002/gcc.20945. [Epub ahead of print]

PMID 22072439

Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation.

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.

Hum Mol Genet. 2006 Jul 1;15(13):2125-37. Epub 2006 May 22.

PMID 16717057

CIC, a gene involved in cerebellar development and ErbB signaling, is significantly expressed in medulloblastomas.

Lee CJ, Chan WI, Scotting PJ.

J Neurooncol. 2005 Jun;73(2):101-8.

PMID 15981098

Translocation (4;19)(q35;q13.1)-associated primitive round cell sarcoma: report of a case and review of the literature.

Rakheja D, Goldman S, Wilson KS, Lenarsky C, Weinthal J, Schultz RA.

Pediatr Dev Pathol. 2008 May-Jun;11(3):239-44. Epub 2007 Jul 16.

PMID 17990934

t(4;19)(q35;q13.1): a recurrent change in primitive mesenchymal tumors?

Richkind KE, Romansky SG, Finklestein JZ.

Cancer Genet Cytogenet. 1996 Mar;87(1):71-4.

PMID 8646746

Pediatric undifferentiated sarcoma of the soft tissues: a clinicopathologic study.

Somers GR, Gupta AA, Doria AS, Ho M, Pereira C, Shago M, Thorner PS, Zielenska M.

Pediatr Dev Pathol. 2006 Mar-Apr;9(2):132-42. Epub 2006 Jun 16.

PMID 16822084

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

Yoshimoto M, Graham C, Chilton-MacNeill S, Lee E, Shago M, Squire J, Zielenska M, Somers GR.

Cancer Genet Cytogenet. 2009 Nov;195(1):1-11.

PMID 19837261

Citation

This paper should be referenced as such :

Graham, C ; Somers, G

t(4;19)(q35;q13) in pediatric undifferentiated soft tissue sarcomas

Atlas Genet Cytogenet Oncol Haematol. 2012;16(4):301-303.

Free journal version : [ pdf ] [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Tumors/t0419q35q13SarcID5714.html

Translocations implicated (Data extracted from papers in the Atlas)

t(4;19)(q35;q13) CIC/DUX4

External links

Mitelman database t(4;19)(q35;q13) [Fusion]     t(4;19)(q35;q13) [Cytogenetics Case]
COSMIC [ CIC ]   [ DUX4 ]

COSMIC_fusion CIC (19q13.2) DUX4 (-)    [fusion1370] [fusion1371] [fusion1372] [fusion1373] [fusion1374] [fusion1375]
Mitelman database CIC/DUX4[Fusion]   CIC (19q13.2) DUX4 (-)

Mitelman database CIC/DUX4[Fusion]   CIC (19q13.2) DUX4 (-)   t(4;19)(q35;q13)

TICdb CIC/DUX4    CIC (19q13.2) DUX4 (10q26.3)

Disease database Soft Tissues: Pediatric undifferentiated sarcoma with t(4;19)(q35;q13)

REVIEW articles automatic search in PubMed

Last year articles automatic search in PubMed

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For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.

ICD-Topo	C470-C476,C478-C479,C490-C496,C498-C499 CONNECTIVE & SOFT TISSUE
ICD-Morpho	9364/3 9260/3 Peripheral neuroectodermal tumor
Atlas_Id	5714
Phylum	Soft Tissues::Pediatric undifferentiated soft tissue sarcoma
WHO/OMS Classification	Soft Tissues

Other names	CIC-DUX4-positive pediatric primitive round cell sarcomas
	Ewing-like sarcomas with t(4;19)(q25;q13) translocation
	CIC fusion with DUX4 in EWSR1-negative undifferentiated small blue round cell sarcomas
	t(4;19)(q35;13.1) in primitive mesenchymal tumors
	Translocation (4;19)(q35;q13.1)-associated primitive round cell sarcomas

Disease	Approximately 5% of sarcomas remain unclassifiable using current diagnostic techniques. These tumors, termed undifferentiated soft tissue sarcomas, show no specific lineage differentiation and exhibit no well established immunohistochemical profile (Somers et al., 2006). Recently, a subclass of undifferentiated sarcomas with primitive round cell morphology were found to harbor a CIC-DUX4 fusion gene resulting from a t(4;19)(q35;q13) rearrangement.
Epidemiology	A total of 8 pediatric cases have been reported to date (Richkind et al., 1996; Rakheja et al., 2008; Yoshimoto et al., 2009; Graham et al., 2011; Italiano et al., 2011). There seems to be no sex predilection as 4 patients were male and 4 patients were female. Tumors occurred in children with a median age of 11.5 years (range 6-16), with no difference between the ages of the males and females.
Clinics	Primary tumors were located in the trunk (n=4), lower extremities (n=3) and head and neck (n=1). Of the 8 patients, 3 patients died as a result of the disease and 5 were alive at last stated follow-up.
Pathology	Tumors are composed of primitive round cells arranged in sheets or nests, with increased nuclear:cytoplasmic ratios. No evidence of differentiation is discernible at the light microscopy level. The majority are positive for CD99 in either a membranous or cytoplasmic pattern of expression.


	Photomicrograph of a primitive round cell sarcoma harbouring a CIC-DUX4 fusion transcript.

Note	This fusion gene cannot always be detected using gross cytogenetic techniques (G-banding/SKY). In at least one case, SKY did not identify the fusion gene, but subsequent FISH and RT-PCR analyses found the case to be positive for the t(4;19)(q35;q13) (Yoshimoto et al., 2009).
Cytogenetics Molecular	Fluorescence in situ hybridization (FISH) with probes for the CIC and DUX4 genes can be used to detect the CIC-DUX4 rearrangement, as it displays fusion of signals on one chromosome.

Gene Name	CIC (capicua transcriptional repressor)
Location	19q13.2
Protein	The human CIC gene is an ortholog of the Drosophila capicua gene, and is a member of the HMG-box superfamily of transcription factors (Lee et al., 2002). This gene has 20 exons encoding a protein of 1608 amino acids, and contains an N-terminal DNA-binding HMG-box and sixteen possible MAPK phosphorylation sites. CIC has been shown to be involved in mediating two oncogenic signalling pathways, EGFR and Wnt, by transcriptional repression (Lee et al., 2005).

Gene Name	DUX4 (double homeobox 4)
Location	4q35.2
Protein	The DUX4 gene is a double-homeobox gene belonging to the family of double homeodomain transcriptional activators. DUX4 is located within the tandem repeat locus D4Z4 on chromosome 4 and contains two DNA-binding homeoboxes at its N-terminus (Gabriels et al., 1999). A similar D4Z4 repeat has been identified on chromosome 10.

Hybrid Gene
Description	5' CIC - 3' DUX4. Fusion of exon 20 of the CIC gene and exon 1 of the DUX4 gene, resulting in an in-frame fusion between CIC and DUX4 with the CIC open reading frame and the DUX4 stop codon. In 5 of the 8 cases the fusion breakpoint was mapped, and 4 distinct breakpoints within exon 20 of CIC and exon 1 of DUX4 were identified (Yoshimoto et al., 2009; Graham et al., 2011).
Fusion Protein
Note	Protein prediction suggests that this fusion leaves intact the majority of the CIC protein functional domains, including the DNA-binding high-mobility group (HMG)-box, and 15 of 16 putative MAPK phosphorylation sites, but results in the loss of the majority of the DUX4 protein functional domains, namely both DNA-binding homeodomains (Graham et al., 2011).

Mitelman database	t(4;19)(q35;q13) [Fusion] t(4;19)(q35;q13) [Cytogenetics Case]
COSMIC	[ CIC ] [ DUX4 ]
COSMIC_fusion	CIC (19q13.2) DUX4 (-) [fusion1370] [fusion1371] [fusion1372] [fusion1373] [fusion1374] [fusion1375]
Mitelman database	CIC/DUX4[Fusion] CIC (19q13.2) DUX4 (-)
Mitelman database	CIC/DUX4[Fusion] CIC (19q13.2) DUX4 (-) t(4;19)(q35;q13)
TICdb	CIC/DUX4 CIC (19q13.2) DUX4 (10q26.3)

Disease database	Soft Tissues: Pediatric undifferentiated sarcoma with t(4;19)(q35;q13)

REVIEW articles	automatic search in PubMed
Last year articles	automatic search in PubMed