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van der Ent et al. J Transl Genet Genom 2018;2:10. I https://doi.org/10.20517/jtgg.2018.09 Page 3 of 12

Table 1. Rare chromosomal rearrangements found in Ewing sarcoma
Rearrangement types Fusion gene Chromosomal rearrangement References
Rearrangement between TET EWSR1-ETV1 t(7;22)(p22;q12) Jeon et al. [40]
and ETS family of genes EWSR1-ETV4 t(17;22)(q21;q12) Urano et al. [41]
EWSR1-FEV t(2;22)(q35;q12) Peter et al. [42]
FUS-ERG t(16;21)(p11;q22) Shing et al. [43]
FUS-FEV t(2;16)(q35;p11) Ng et al. [44]
Rearrangement between TET EWSR1-NFATC2 t(20;22)(q13;q12) Szuhai et al. [45]
and non-ETS family of genes EWSR1-POU5F1 t(20;22)(p21;q12) Yamaguchi et al. [46]
EWSR1-SMARCA5 t(4;22)(q31;q12) Sumegi et al. [47]
EWSR1-PATZ t(1;22)(p36.1;q12)[with inv(22)] Mastrangelo et al. [48]
EWSR1-SP3 t(2;22)(q31;q12) Wang et al. [49]
Rearrangement between non- CIC-DUX4 t(4;19)(q35;q13) Kawamura-Saito et al. [38]
TET and non-ETS family of CIC-FOXO4 t(X;19)(q13;q13.3) Brohl et al. [50]
genes Sugita et al. [51]
BCOR-CCNB3 inv(X)(p11.4p11.22) Pierron et al. [39]
BCOR-MAML3 t(x;4)(p11.4;q31.1) Specht et al. [52]
ZC3H7B-BCOR Specht et al. [52]
CRTC1-SS18 Alholle et al. [53]

factor family have been identified. In some cases, tumours with histological, radiological and clinical fea-
tures are identified without rearrangement between TET members and ETS members. These “Ewing-like”
tumours do bear other chromosomal translocations, such as the CIC-DUX4 or BCOR-CCNB3 [38,39] . An over-
view of these rarer types of translocation found in EWS is given in Table 1 [38-53] .

Copy number alterations
Besides the characteristic EWSR1-ETS translocation, chromosomal copy number alterations have been de-
scribed with various implications for clinical outcome. Trisomy of chromosome 8 occurs in about 35%-45%
of all cases, gain of chromosome 12 in 25%-33% [54-57] ; these gains can occur together or separately, and are
more likely to be found in relapses than in primary tumours. Chromosome 8 gain confers no significant
prognostic value, while gain of chromosome 12 has been reported to associate with adverse effects in patients
[58]
with localised disease . Gain of chromosome 2 is primarily found in localised tumours and may indicate a
[59]
positive prognosis .
An unbalanced der(16)t(1;16) translocation leading to partial tri- or tetrasomy of 1q and partial monosomy of
16 is found in 10%-30% of cases [54,57,60,61] . Gain of 1q was repeatedly correlated to an adverse clinical pronosis.
Overexpression of cell division cycle protein 2 (CDT2), encoding a protein involved in the ubiquitin ligase
[62]
activity and DNA damage repair, is suggested to underlie this aggressive phenotype .
[63]
After 16q, loss of 9p21 is most frequently observed, and results in a poor clinical outcome . A reason for
this may be the loss of cyclin-dependent kinase Inhibitor 2A (CDKN2A), present at this locus.

Mutations
Studies investigating the genomic landscape of EWS highlight the paucity of recurrent somatic mutations
in this cancer [50,64,65] . Mutation or downregulation of CDKN2A is reported in 10%-30% of EWS cases [66-70] .
Encoding P16 INK4A , loss of CDKN2A has been shown to correlate with a poor prognosis [67,68,71] , though a later
study has stated that it is not a reliable prognostic marker for localised EWS . TP53 has also been shown to
[72]
[73]
lead to a poor prognosis, although these mutations are infrequent (less than 15% of cases) , and also a non-
[72]
reliable prognostic marker for localised disease .
Inactivating mutations in STAG2 are reported in 9%-21% of EWS cases [74,75] , appear to be mutually exclu-
[64]
sive with CDKN2A, while co-associating with TP53 mutations and poor patient prognosis . STAG2 is an
oncogene recurrently mutated in various cancer types . As a member of the cohesion complex, it helps in
[76]