STBT5:Ewing sarcoma

Soft Tissue and Bone Tumours (Who Classification, 5th ed.)

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

Primary Author(s)*

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WHO Classification of Disease

Structure	Disease
Book	Soft Tissue and Bone Tumours (5th ed.)
Category	Undifferentiated small round cell sarcomas of bone and soft tissue
Family	N/A
Type	Ewing sarcoma
Subtype(s)	N/A

Related Terminology

Acceptable	N/A
Not Recommended	Askin tumour (for Ewing sarcoma arising in the chest wall); primitive neuroectodermal tumour

Note: Some small round cell sarcomas previously considered subtypes of Ewing sarcoma (Ewing-like sarcomas) are genetically and clinically distinct entities and include CIC-rearranged sarcoma and sarcoma with BCOR genetic alterations, described in separate sections.

Gene Rearrangements

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Ewing sarcoma is defined by fusions between a FET family gene (usually EWSR1 or rarely FUS/TAF15) and a member of the ETS family of transcription factors. These chimeric oncoproteins act as aberrant transcription factors and are required for tumorigenesis. Rare variant fusions involving non ETS partners have also been described.

Driver Gene	Fusion(s) and Common Partner Genes	Molecular Pathogenesis	Typical Chromosomal Alteration(s)	Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EWSR1	EWSR1::FLI1	FET–ETS chimeric transcription factor; binds GGAA microsatellites and canonical ETS sites, recruits chromatin regulators, opens closed chromatin to establish de novo enhancers and represses wild-type ETS targets, driving an oncogenic gene-expression program.	Classically t(11;22)(q24;q12); usually balanced but can be unbalanced or cryptic (e.g. insertional events).	Common (~85% of Ewing sarcomas)	D	Yes (WHO, NCCN)	The t(11;22)(q24;q12) rearrangement resulting in EWSR1::FLI1 is diagnostic of Ewing sarcoma in the appropriate clinical and morphological context (PMID: 1522903). This is the most common fusion, occurring in ~85% of cases. Although several transcript variants exist (e.g., Type 1 and Type 2), fusion subtype does not alter current management and is not used for risk stratification in modern protocols. Rare cryptic insertional variants may be FISH-negative, requiring RNA-based sequencing for detection
EWSR1	EWSR1::ERG	EXAMPLE: Typically, the last exon of CIC is fused to DUX4. The fusion breakpoint in CIC is usually intra-exonic and removes an inhibitory sequence, upregulating PEA3 genes downstream of CIC including ETV1, ETV4, and ETV5.	t(21;22)(q22;q12) or complex/unbalanced rearrangements involving 21q22 and 22q12.	Recurrent (~10% of Ewing sarcomas)	D (±P)	Yes (WHO, NCCN)	EXAMPLE: EWSR1::ERG accounts for ~10% of Ewing sarcomas and is most commonly produced through complex or unbalanced rearrangements. These structural variants can result in false-negative EWSR1 break-apart FISH, making ERG-specific FISH or RNA-based NGS essential when morphology and immunophenotype suggest Ewing sarcoma. Clinical behavior appears broadly similar to EWSR1::FLI1 fusions, although chromoplexy-associated cases show increased TP53 mutations in some series
EWSR1	EWSR1::ETV1 Other fusion partners include ETV4, FEV, E1AF, ZSG	EXAMPLE: Fusions result in constitutive activation of the ALK tyrosine kinase. The most common ALK fusion is EML4::ALK, with breakpoints in intron 19 of ALK. At the transcript level, a variable (5’) partner gene is fused to 3’ ALK at exon 20. Rarely, ALK fusions contain exon 19 due to breakpoints in intron 18.	Various balanced or complex translocations/insertions involving ETS loci (7p21 for ETV1, 17q21 for ETV4, 2q36 for FEV). t(7;22)(p22;q12) t(2;22)(q33;q12) t(17;22)(q12;q12) inv(22)(q12q12)	Rare (<5% of Ewing sarcomas)	D (±P)	Yes (WHO, NCCN)	These rare FET–ETS fusions are diagnostic of Ewing sarcoma when identified in the correct clinical setting. All functionally mimic EWSR1::FLI1 by generating a chimeric ETS transcription factor that drives an oncogenic enhancer program. FEV-rearranged tumors may present in older patients, show a higher frequency of extraskeletal disease, and may be associated with more aggressive clinical behavior in limited published cohorts. ETV1/ETV4 fusions have been reported in very young children (<2 years).
FUS	FUS::ERG Other fusion partners include FEV	FUS substitutes for EWSR1 within the FET family, forming FET–ETS fusion proteins with the same GGAA-microsatellite–driven chromatin reprogramming mechanism.	t(16;21)(p11;q22) Translocations involving 16p11 (FUS) and ETS loci (21q22 ERG, 2q36 FEV); balanced or complex.	Rare (<5% of Ewing sarcomas)	D (±P)	Yes (WHO, NCCN)	FUS-based fusions represent rare (<5%) molecular subsets of Ewing sarcoma in which FUS substitutes for EWSR1 within the FET family. Their presence confirms the diagnosis in cases lacking EWSR1 rearrangements. As with EWSR1-ERG, FUS-ERG cases may involve complex rearrangements that require RNA-based NGS for detection. FUS::FEV–positive tumors may show predilection for extraskeletal sites and worse outcomes compared to classic ES fusions in small studies.
TAF15	TAF15::ETS	FET-family member forming FET–ETS chimeric transcription factors with analogous chromatin and transcriptional effects.	Various translocations involving 17q12 (TAF15) and ETS loci.	Rare (<5% of Ewing sarcomas)	D	Yes (WHO)	TAF15–ETS fusions occur rarely and are considered genetic equivalents to EWSR1- and FUS-based FET–ETS rearrangements. Their identification supports a diagnosis of Ewing sarcoma when morphology and phenotype are appropriate. Because many TAF15 rearrangements are cryptic, RNA sequencing is often required. No distinct prognostic or therapeutic implications apart from those of conventional Ewing sarcoma are currently recognized.

Individual Region Genomic Gain/Loss/LOH

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These copy-number alterations represent secondary genomic events that accompany the primary FET–ETS fusion. They are thought to reflect genome instability, replication stress buffering, or clonal selection, rather than defining molecular subtypes.

According to the WHO classification, the prognostic role of copy-number alterations remains under prospective validation.

https://pubmed.ncbi.nlm.nih.gov/41301081/)

Chr #	Gain, Loss, Amp, LOH	Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]	Relevant Gene(s)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
1	Gain	1q21-q44 (arm-level); chr1q [hg38; ~90 Mb]	Multiple (e.g., RAD21, MDM4)	P	No	Recurrent arm-level gain, frequently occurring with concurrent 16q loss; reflects increased copy-number burden and genomic instability.
16	Loss	-16q11-q24 (arm-level); chr16q [hg38; ~45 Mb]	Multiple	P	No	Often paired with 1q gain as part of an unbalanced t(1;16); associated with inferior outcome in some cohorts.
8	Gain	Whole chromosome 8; chr8 [hg38; ~146 Mb]	RAD21, MYC (8q24)	P (uncertain)	No	One of the most frequent numerical aberrations; increased RAD21 dosage may mitigate replication stress driven by EWSR1::FLI1; prognostic impact is variable.
12	Gain	Whole chromosome 12; chr12 [hg38; ~134 Mb]	None recurrently amplified	P (uncertain)	No	Recurrent trisomy reflecting mitotic mis-segregation; focal MDM2 or CDK4 amplification is not typical of Ewing sarcoma.
20	Gain	Whole chromosome 20; chr20 [hg38; ~64 Mb]	Multiple	P (uncertain)	No	Less frequent whole-chromosome gain; clinical significance remains unclear.
9	Loss	9p21.3; [hg38; ~1 Mb]	CDKN2A, CDKN2B	P (uncertain)	No	Focal homozygous deletions remove key cell-cycle regulators; prognostic relevance remains under prospective validation.
11	LOH	11q24-q25 (region including FLI1)	FLI1 (partner locus)	P	No	May arise near the fusion partner locus through local structural complexity; reflects genomic instability rather than a distinct subtype.
22	LOH	22q12 (region including EWSR1)	EWSR1	P	No	Copy-number changes adjacent to the fusion locus may accompany complex rearrangements or chromoplexy events.

Characteristic Chromosomal or Other Global Mutational Patterns

Put your text here and fill in the table (Instructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.) Beyond the primary FET–ETS fusion, recurrent numerical and structural aberrations (listed above) reflect genome instability rather than distinct tumour subtypes. The presence of metastases at diagnosis remains the most powerful prognostic factor.

Chromosomal Pattern	Molecular Pathogenesis	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
Hyperdiploidy / numerical chromosomal gains	Mitotic mis-segregation leading to whole-chromosome gains	Recurrent	P	No	Frequently observed secondary event; reflects chromosomal instability rather than a distinct biological subtype.
Gain of odd-numbered chromosomes (e.g., 1, 7, 8, 12)	Whole-chromosome gains arising from aneuploidy	Recurrent	P (uncertain)	No	Includes recurrent gains of chromosomes 1q, 8, and 12; prognostic impact varies across cohorts.
1q gain with 16q loss	Unbalanced translocation, most commonly t(1;16), resulting in arm-level copy-number imbalance	Common	P	No	One of the most frequent structural patterns; associated with increased copy-number burden and adverse outcome in some studies.
Complex karyotype / multiple copy-number alterations	Accumulation of secondary structural and numerical aberrations during tumor evolution	Recurrent	P	No	Reflects genomic instability accompanying disease progression rather than defining a molecular subgroup.
Chromoplexy / clustered rearrangements near fusion loci	Coordinated DNA breakage and rejoining events involving multiple chromosomal regions	Recurrent	P	No	Often involves regions flanking EWSR1 and ETS partner genes; considered an early or progression-related genomic phenomenon.
Microsatellite instability (MSI)	Defective mismatch repair	Rare	None	No	MSI-high phenotype is not a characteristic feature of Ewing sarcoma.
Chromothripsis	Single catastrophic chromosomal shattering event	Rare	P (uncertain)	No	Reported in isolated cases; clinical significance remains unclear.
Homologous recombination deficiency	Impaired DNA double-strand break repair	Rare	None	No	Not a defining feature of Ewing sarcoma.

Gene Mutations (SNV/INDEL)

Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Gene	Genetic Alteration	Tumor Suppressor Gene, Oncogene, Other	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
STAG2	LOF mutations or deletions	Tumor Supressor Gene	Recurrent	P	EXAMPLE: Yes (NCCN)	Loss may confer chromosomal instability; associated with increased relapse risk in some studies.
CDKN2A	Homozygous deletion	Tumor Supressor Gene	Recurrent	P		Coincides with 9p21 focal deletion; prognostic impact inconsistent
TP53	Pathogenic missense mutations	Tumor Supressor Gene	Recurrent	P		Rare; may indicate aggressive disease, may co‑occur with STAG2 alterations

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Epigenomic Alterations

Put your text here FET–ETS fusion proteins act as aberrant transcription factors that broadly dysregulate gene expression. They bind GGAA microsatellites and canonical ETS binding sites, promoting a transition from closed to open chromatin through the establishment of de novo enhancers while displacing wild-type ETS factors at native regulatory elements. Together, these effects create a dominant oncogenic gene expression program that underlies tumor initiation. Although secondary epigenetic regulators, including chromatin modifiers and demethylases, have been implicated in the literature, their roles are not detailed in the WHO classification.

Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EWSR1::FLI1 and other FET–ETS fusions	Transcriptional regulation via aberrant ETS binding	Establishes de novo enhancers and represses native ETS targets, resulting in a dominant oncogenic gene-expression program that initiates tumor development.
STAG2 (LOF)	Cohesin complex, chromatin organization	Disruption of cohesin function leads to chromosomal instability and altered enhancer–promoter interactions; associated with adverse clinical outcome in some cohorts.
CDKN2A (homozygous deletion or inactivating mutations)	Cell‑cycle regulation	Loss of p16INK4a/p14ARF promotes unchecked cell cycle progression; prognostic relevance remains under prospective evaluation.
TP53 (pathogenic missense mutations)	DNA damage response and apoptosis	Impaired cell cycle arrest and apoptotic signaling, may be associated with aggressive disease behavior.

Genetic Diagnostic Testing Methods

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Histopathology and IHC: Sheets of small round cells with strong membranous CD99 expression are characteristic; NKX2‑2, FLI1 and ERG expression may support diagnosis.

FISH: Ideally dual-color dual fusion for EWSR1 and common partner, but most institutions carry Dual‑color break‑apart probes for EWSR1 or FUS detect most rearrangements; however, complex inversions, insertions or rare partner fusions may escape detection.

RNA‑based assays (RT‑PCR or next‑generation sequencing): Necessary to identify specific fusion partners and to detect cryptic fusions negative by break‑apart FISH.

Copy‑number analysis: Low‑pass whole‑genome sequencing or cytogenomic microarrays can detect recurrent gains and losses (e.g., 1q gain/16q loss, trisomy 8, trisomy 12, CDKN2A deletion). Prognostic use of these CNAs is under investigation

Familial Forms

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Ewing sarcoma is primarily sporadic. Rare germline predisposition is noted in some cases, but no specific syndromes are detailed in the WHO guidelines. Investigations into germline variants (e.g., DNA repair genes) are ongoing.

Additional Information

Put your text here Prognosis: The presence of metastases at diagnosis and anatomical site (e.g., pelvic lesions) remain the strongest prognostic indicators. Copy‑number burden (e.g., 1q gain/16q loss) and mutations such as STAG2, CDKN2A and TP53 may contribute to risk stratification, but their significance is still being validated

pmc.ncbi.nlm.nih.gov

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Treatment considerations: Current therapy consists of multi‑agent chemotherapy combined with surgery and/or radiation. No targeted agents are specifically approved for Ewing sarcoma in the WHO guideline; however, research is exploring personalized therapy, and clinical trials are exploring targeted and epigenetic therapies.

Links

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https://tumourclassification.iarc.who.int/welcome/

https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1464

References

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https://pubmed.ncbi.nlm.nih.gov/41301081/

Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the Associate Editor or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s): *Citation of this Page: “Ewing sarcoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/3/2026, https://ccga.io/index.php/STBT5:Ewing sarcoma.