Download Solid Tumour Section t(4;19)(q35;q13) in pediatric undifferentiated soft tissue sarcomas

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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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.
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