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features and biomarkers, in the past it has been ascribed to endothelial, reticuloendothelial, hematopoietic,
[3-5]
neural crest and mesenchymal cells . Currently, the view is that EWS arises from a progenitor or stem cell
derived from neural crest or mesenchymal cells. The main sites of involvement are the long bones, pelvis and
ribs (~85% of all cases), and lower extremities and the paravertebral region in cases of extra skeletal involve-
[1,6]
ment (~15%) .

Overall survival rates of EWS patients with localised disease have starkly improved since the introduction
[7]
of systemic therapy to the treatment regime . Patients with localised disease currently have an overall event
[8]
free survival of 60%-70% . In a quarter of patients, metastatic disease is observed at the time of diagnosis.
These patients have an unfavourable prognosis, with overall event free survival of 20%-30% [9-12] . Patients who
solely have lung-metastases seem to fare somewhat better than patients with metastases in bone or bone-
marrow [13,14] .

Standard protocol for treatment of EWS upon diagnosis is chemotherapy followed by surgical resection and/
or radiotherapy [15,16] . In Europe, the chemotherapeutic regime consists of multiple cycles of vincristine, ifos-
famide, doxorubicin and etoposide [16,17] .

GENETIC ALTERATIONS
Chromosomal translocations
In 85% of all EWS cases, there is a reciprocal t(11;22)(q24;q12) translocation, merging ES Breakpoint region
[18]
1 (EWSR1) to Friend leukaemia virus integration site 1 (FLI1) . The fusion of EWSR1 with ERG, t(21;22)
(q11;q12), makes up for another 10% of EWS cases [19,20] . Both FLI1 and ERG are members of the erythroblast
transformation-specific (ETS) transcription factor family and share a conserved DNA binding domain
structure. Fusion of the N-terminal region of EWSR1, which contains a strong transcriptional activation do-
main [21,22] , and these DNA binding domains causes aberrant transcription of a multitude of genes. Addition-
[27]
ally, EWSR1-ETS is known to affect epigenetic programs [23,24] , splicing [25,26] , and metabolic activity of EWS.
Oncogenic fusions between ETS genes and transcriptional activators are not unique to EWS: in 50%-70% of
[28]
prostate cancers, similar chromosomal rearrangements are found .

The breakpoint position varies, and commonly occurs between exons 7-11 for EWSR1 and exons 4-9 for
FLI1, leading to variations in fusion types between patients with EWSR1-FLI1. The most common type is a
fusion between EWSR1 exons 1-7 and FLI1 exons 6-9, a type 1 fusion, or EWSR1 exons 1-7 and FLI1 exons 5-9,
a type 2 fusion. The effect of these variations in the oncogene on its function has been debated. While some
studies observe differences in malignancy between fusion types [29,30] , a European prospective trial found no
[31]
prognostic significance between them . Different fusion types were shown to have a different dependence
on various proteins of the splicing machinery, so inhibition of splicing factors may have therapeutic value in
[32]
some cases of EWS .

As the only consistent genetic alteration, among the very few found in EWS in general, EWSR1-FLI1 has
been the main player in the attempts to develop in vitro and in vivo models for the disease. However, de-
[33]
velopment of transgenic mouse-models is hampered by toxicity of EWSR1-FLI1 to most cells . Additional
genetic variations may be needed to create a permissive environment, implied by the bias of disease occur-
[1]
rence in Caucasians . A recent GWAS identified 3 EWS-associated single nucleotide polymorphisms (SNPs),
[34]
near EGR2, BMF and TARDBP genes . At the locus near EGR2, the causative SNP links two GGAA repeat
[35]
stretches . In addition to classic ETS transcription factor binding sites, EWSR1-FLI1 preferentially binds to
such stretches of GGAA repeats, where its activity increases with the increase of amount of repeats [36,37] .

In addition to the more common EWSR1-FLI1 and EWSR1-ERG translocation events, other fusions between
members of the TET family of proteins (including EWSR1 and FUS) and members of the ETS transcription