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

2011-11-01   Cassandra Graham , Gino Somers 

1.Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, M5G 1X8, ON, Canada

Clinics and Pathology

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

Cytogenetics

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.

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).

Genes Involved and Proteins

Gene name

CIC (capicua transcriptional repressor)

Location

19q13.2

Protein description

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 description

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

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).

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

Note

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

Pubmed IDLast YearTitleAuthors
104339631999Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element.Gabriëls J et al
218131562012The CIC-DUX4 fusion transcript is present in a subgroup of pediatric primitive round cell sarcomas.Graham C et al
220724392012High prevalence of CIC fusion with double-homeobox (DUX4) transcription factors in EWSR1-negative undifferentiated small blue round cell sarcomas.Italiano A et al
167170572006Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation.Kawamura-Saito M et al
159810982005CIC, a gene involved in cerebellar development and ErbB signaling, is significantly expressed in medulloblastomas.Lee CJ et al
179909342008Translocation (4;19)(q35;q13.1)-associated primitive round cell sarcoma: report of a case and review of the literature.Rakheja D et al
86467461996t(4;19)(q35;q13.1): a recurrent change in primitive mesenchymal tumors?Richkind KE et al
168220842006Pediatric undifferentiated sarcoma of the soft tissues: a clinicopathologic study.Somers GR et al
198372612009Detailed cytogenetic and array analysis of pediatric primitive sarcomas reveals a recurrent CIC-DUX4 fusion gene event.Yoshimoto M et al

Citation

Cassandra Graham ; Gino Somers

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

Atlas Genet Cytogenet Oncol Haematol. 2011-11-01

Online version: http://atlasgeneticsoncology.org/solid-tumor/5714/soft-tissues-pediatric-undifferentiated-sarcoma-with-t(4;19)(q35;q13)