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)*

Put your text here (EXAMPLE: Jane Smith, PhD)

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

Put your text here and fill in the table (Instructions: 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.)

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 programme.	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 programme. 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

Put your text here and fill in the table (Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.)

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
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7	EXAMPLE: Unknown	EXAMPLE: D, P	EXAMPLE: No	EXAMPLE: Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references).
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8	EXAMPLE: Unknown	EXAMPLE: D, P		EXAMPLE: Common recurrent secondary finding for t(8;21) (add references).
EXAMPLE: 17	EXAMPLE: Amp	EXAMPLE: 17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]	EXAMPLE: ERBB2	EXAMPLE: D, P, T		EXAMPLE: Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.

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.)

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
EXAMPLE: Co-deletion of 1p and 18q	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).	EXAMPLE: Common (Oligodendroglioma)	EXAMPLE: D, P
EXAMPLE: Microsatellite instability - hypermutated		EXAMPLE: Common (Endometrial carcinoma)	EXAMPLE: P, T

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
EXAMPLE:EGFR	EXAMPLE: Exon 18-21 activating mutations	EXAMPLE: Oncogene	EXAMPLE: Common (lung cancer)	EXAMPLE: T	EXAMPLE: Yes (NCCN)	EXAMPLE: Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
EXAMPLE: TP53; Variable LOF mutations	EXAMPLE: Variable LOF mutations	EXAMPLE: Tumor Supressor Gene	EXAMPLE: Common (breast cancer)	EXAMPLE: P		EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
EXAMPLE: BRAF; Activating mutations	EXAMPLE: Activating mutations	EXAMPLE: Oncogene	EXAMPLE: Common (melanoma)	EXAMPLE: T

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

Genes and Main Pathways Involved

Put your text here and fill in the table (Instructions: Please include references throughout the table. Do not delete the table.)

Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE: KMT2C and ARID1A; Inactivating mutations	EXAMPLE: Histone modification, chromatin remodeling	EXAMPLE: Abnormal gene expression program

Genetic Diagnostic Testing Methods

Put your text here (Instructions: Include recommended testing type(s) to identify the clinically significant genetic alterations.)

Familial Forms

Put your text here (Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.)

Additional Information

Put your text here

Links

Put a link here or anywhere appropriate in this page (Instructions: Highlight the text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the wiki page, and search the name of the internal page to which you want to link this text, or enter an external internet address by including the "http://www." portion.)

References

(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted.)

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 11/30/2025, https://ccga.io/index.php/STBT5:Ewing sarcoma.