Compendium of Cancer Genome Aberrations

STBT5:Ewing sarcoma: Difference between revisions

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==Gene Rearrangements==
==Gene Rearrangements==
Put your text here and fill in the table <span style="color:#0070C0">(''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.'')</span>
Put your text here and fill in the table <span style="color:#0070C0">(''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.'')</span>
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.
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
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!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''ABL1''||<span class="blue-text">EXAMPLE:</span> ''BCR::ABL1''||<span class="blue-text">EXAMPLE:</span> The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.||<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)
|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).
|<span class="blue-text">EXAMPLE:</span> Common (CML)
|Common (~85% of Ewing sarcomas)
|<span class="blue-text">EXAMPLE:</span> D, P, T
|D
|<span class="blue-text">EXAMPLE:</span> Yes (WHO, NCCN)
|Yes (WHO, NCCN)
|<span class="blue-text">EXAMPLE:</span>
|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
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). BCR::ABL1 is generally favorable in CML (add reference).
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''CIC''
|EWSR1
|<span class="blue-text">EXAMPLE:</span> ''CIC::DUX4''
|''EWSR1::ERG''
|<span class="blue-text">EXAMPLE:</span> 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''.
|<span class="blue-text">EXAMPLE:</span> 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''.
|<span class="blue-text">EXAMPLE:</span> t(4;19)(q25;q13)
|t(21;22)(q22;q12) or complex/unbalanced rearrangements involving 21q22 and 22q12.
|<span class="blue-text">EXAMPLE:</span> Common (CIC-rearranged sarcoma)
|Recurrent (~10% of Ewing sarcomas)
|<span class="blue-text">EXAMPLE:</span> D
|D (±P)
|
|Yes (WHO, NCCN)
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>


''DUX4'' has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).
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
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''ALK''
|''EWSR1''
|<span class="blue-text">EXAMPLE:</span> ''ELM4::ALK''
|''EWSR1::ETV1''




Other fusion partners include ''KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1''
Other fusion partners include ''ETV4, FEV, E1AF, ZSG''
|<span class="blue-text">EXAMPLE:</span> 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.
|<span class="blue-text">EXAMPLE:</span> 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.
|<span class="blue-text">EXAMPLE:</span> N/A
|Various balanced or complex translocations/insertions involving ETS loci (7p21 for ETV1, 17q21 for ETV4, 2q36 for FEV).
|<span class="blue-text">EXAMPLE:</span> Rare (Lung adenocarcinoma)
t(7;22)(p22;q12)
|<span class="blue-text">EXAMPLE:</span> T
t(2;22)(q33;q12)
|
t(17;22)(q12;q12)
|<span class="blue-text">EXAMPLE:</span>
inv(22)(q12q12)
 
|Rare (<5% of Ewing sarcomas)
Both balanced and unbalanced forms are observed by FISH (add references).
|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).
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''ABL1''
|''FUS''
|<span class="blue-text">EXAMPLE:</span> N/A
|FUS::ERG
|<span class="blue-text">EXAMPLE:</span> Intragenic deletion of exons 2–7 in ''EGFR'' removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways.
Other fusion partners include FEV
|<span class="blue-text">EXAMPLE:</span> N/A
|FUS substitutes for EWSR1 within the FET family, forming FET–ETS fusion proteins with the same GGAA-microsatellite–driven chromatin reprogramming mechanism.
|<span class="blue-text">EXAMPLE:</span> Recurrent (IDH-wildtype Glioblastoma)
|t(16;21)(p11;q22)
|<span class="blue-text">EXAMPLE:</span> D, P, T
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==
==Individual Region Genomic Gain/Loss/LOH==
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!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>''EGFR''
|''STAG2''


<br />
<br />
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
|LOF mutations or deletions
|<span class="blue-text">EXAMPLE:</span> Oncogene
|<span class="blue-text">EXAMPLE:</span> Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
|Recurrent
|<span class="blue-text">EXAMPLE:</span> T
|<span class="blue-text">EXAMPLE:</span> T
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|<span class="blue-text">EXAMPLE:</span> 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).
|<span class="blue-text">EXAMPLE:</span> 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).
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
|<span class="blue-text">EXAMPLE:</span> CDKN2A''TP53''; Variable LOF mutations
<br />
<br />
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
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