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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Solid Tumour Section Short Communication t(4;19)(q35;q13) in pediatric undifferentiated soft tissue sarcomas Cassandra Graham, Gino Somers Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, M5G 1X8, ON, Canada (CG, GS) Published in Atlas Database: November 2011 Online updated version : http://AtlasGeneticsOncology.org/Tumors/t0419q35q13SarcID5714.html DOI: 10.4267/2042/47309 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology 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. Identity 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 EWSR1negative 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 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. Clinics and pathology Pathology Disease 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. 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. Genetics Note This fusion gene has been identified using various molecular genetic and cytogenetic methods including real-time polymerase chain reaction (RT-PCR), Gbanding, Spectral Karyotyping (SKY) and Fluorescence in situ hybridization (FISH). 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). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(4) 301 t(4;19)(q35;q13) in pediatric undifferentiated soft tissue sarcomas Graham C, Somers G Photomicrograph of a primitive round cell sarcoma harbouring a CIC-DUX4 fusion transcript. 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). 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). DUX4 (double-homeobox 4) Location 4q35 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 DNAbinding homeoboxes at its N-terminus (Gabriels et al., 1999). A similar D4Z4 repeat has been identified on chromosome 10. 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 Result of the chromosomal anomaly CIC (capicua homolog) Location 19q13 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 Atlas Genet Cytogenet Oncol Haematol. 2012; 16(4) 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 302 t(4;19)(q35;q13) in pediatric undifferentiated soft tissue sarcomas Graham C, Somers G Lee CJ, Chan WI, Cheung M, Cheng YC, Appleby VJ, Orme AT, Scotting PJ. CIC, a member of a novel subfamily of the HMG-box superfamily, is transiently expressed in developing granule neurons. Brain Res Mol Brain Res. 2002 Oct 15;106(12):151-6 breakpoints within exon 20 of CIC and exon 1 of DUX4 were identified (Yoshimoto et al., 2009; Graham et al., 2011). Fusion Protein Lee CJ, Chan WI, Scotting PJ. CIC, a gene involved in cerebellar development and ErbB signaling, is significantly expressed in medulloblastomas. J Neurooncol. 2005 Jun;73(2):101-8 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). 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. Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation. Hum Mol Genet. 2006 Jul 1;15(13):2125-37 Somers GR, Gupta AA, Doria AS, Ho M, Pereira C, Shago M, Thorner PS, Zielenska M. Pediatric undifferentiated sarcoma of the soft tissues: a clinicopathologic study. Pediatr Dev Pathol. 2006 Mar-Apr;9(2):132-42 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). Rakheja D, Goldman S, Wilson KS, Lenarsky C, Weinthal J, Schultz RA. Translocation (4;19)(q35;q13.1)-associated primitive round cell sarcoma: report of a case and review of the literature. Pediatr Dev Pathol. 2008 May-Jun;11(3):239-44 Yoshimoto M, Graham C, Chilton-MacNeill S, Lee E, Shago M, Squire J, Zielenska M, Somers GR. Detailed cytogenetic and array analysis of pediatric primitive sarcomas reveals a recurrent CIC-DUX4 fusion gene event. Cancer Genet Cytogenet. 2009 Nov;195(1):1-11 Graham C, Chilton-Macneill S, Zielenska M, Somers GR. The CIC-DUX4 fusion transcript is present in a subgroup of pediatric primitive round cell sarcomas. Hum Pathol. 2011 Aug 1; References Richkind KE, Romansky SG, Finklestein JZ. t(4;19)(q35;q13.1): a recurrent change in primitive mesenchymal tumors? Cancer Genet Cytogenet. 1996 Mar;87(1):71-4 Italiano A, Sung YS, Zhang L, Singer S, Maki RG, Coindre JM, Antonescu CR. High prevalence of CIC fusion with doublehomeobox (DUX4) transcription factors in EWSR1-negative undifferentiated small blue round cell sarcomas. Genes Chromosomes Cancer. 2011 Nov 10; Gabriëls J, Beckers MC, Ding H, De Vriese A, Plaisance S, van der Maarel SM, Padberg GW, Frants RR, Hewitt JE, Collen D, Belayew A. Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element. Gene. 1999 Aug 5;236(1):2532 Atlas Genet Cytogenet Oncol Haematol. 2012; 16(4) This article 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. 303