Compendium of Cancer Genome Aberrations

STBT5:Infantile fibrosarcoma: Difference between revisions

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!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
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|''NTRK3''||''ETV6''||<span class="blue-text">EXAMPLE:</span> The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.||t(12;15)(p13;q25)
|''NTRK3''||''ETV6''||In-frame fusion that results in constitutive activation of the NTRK3 tyrosine kinase domain through heterodimerization and transphosphorylation of the helix-loop-helix domain of ETV6. Breakpoints typically involves exon 5 of ''ETV6'' (NM_001987.4) and exons 14 or 15 of ''NTRK3'' (NM_001243101.1).<ref name=":6">{{Cite journal|last=Church|first=Alanna J.|last2=Calicchio|first2=Monica L.|last3=Nardi|first3=Valentina|last4=Skalova|first4=Alena|last5=Pinto|first5=Andre|last6=Dillon|first6=Deborah A.|last7=Gomez-Fernandez|first7=Carmen R.|last8=Manoj|first8=Namitha|last9=Haimes|first9=Josh D.|date=2018-03|title=Recurrent EML4-NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy|url=https://pubmed.ncbi.nlm.nih.gov/29099503|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=31|issue=3|pages=463–473|doi=10.1038/modpathol.2017.127|issn=1530-0285|pmid=29099503}}</ref>||t(12;15)(p13;q25)
|Common
|Common
|D, T
|D, T
|Yes (WHO, NCCN)
|Yes (WHO, NCCN)
|<span class="blue-text">EXAMPLE:</span>
|The ''ETV6::NTRK3'' fusion [t(12;15)] is diagnostic of infantile fibrosarcoma in the appropriate morphology and clinical context.<ref>{{Cite journal|last=Caldwell|first=Kenneth J.|last2=De La Cuesta|first2=Esther|last3=Morin|first3=Cara|last4=Pappo|first4=Alberto|last5=Helmig|first5=Sara|date=2020-09|title=A newborn with a large NTRK fusion positive infantile fibrosarcoma successfully treated with larotrectinib|url=https://pubmed.ncbi.nlm.nih.gov/32452122|journal=Pediatric Blood & Cancer|volume=67|issue=9|pages=e28330|doi=10.1002/pbc.28330|issn=1545-5017|pmid=32452122}}</ref><ref>{{Cite journal|last=Church|first=Alanna J.|last2=Calicchio|first2=Monica L.|last3=Nardi|first3=Valentina|last4=Skalova|first4=Alena|last5=Pinto|first5=Andre|last6=Dillon|first6=Deborah A.|last7=Gomez-Fernandez|first7=Carmen R.|last8=Manoj|first8=Namitha|last9=Haimes|first9=Josh D.|date=2018-03|title=Recurrent EML4-NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy|url=https://pubmed.ncbi.nlm.nih.gov/29099503|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=31|issue=3|pages=463–473|doi=10.1038/modpathol.2017.127|issn=1530-0285|pmid=29099503}}</ref><ref>{{Cite journal|last=Wegert|first=Jenny|last2=Vokuhl|first2=Christian|last3=Collord|first3=Grace|last4=Del Castillo Velasco-Herrera|first4=Martin|last5=Farndon|first5=Sarah J.|last6=Guzzo|first6=Charlotte|last7=Jorgensen|first7=Mette|last8=Anderson|first8=John|last9=Slater|first9=Olga|date=2018-06-18|title=Recurrent intragenic rearrangements of EGFR and BRAF in soft tissue tumors of infants|url=https://pubmed.ncbi.nlm.nih.gov/29915264|journal=Nature Communications|volume=9|issue=1|pages=2378|doi=10.1038/s41467-018-04650-6|issn=2041-1723|pmc=6006309|pmid=29915264}}</ref><ref>{{Cite journal|last=Rubin|first=B. P.|last2=Chen|first2=C. J.|last3=Morgan|first3=T. W.|last4=Xiao|first4=S.|last5=Grier|first5=H. E.|last6=Kozakewich|first6=H. P.|last7=Perez-Atayde|first7=A. R.|last8=Fletcher|first8=J. A.|date=1998-11|title=Congenital mesoblastic nephroma t(12;15) is associated with ETV6-NTRK3 gene fusion: cytogenetic and molecular relationship to congenital (infantile) fibrosarcoma|url=https://pubmed.ncbi.nlm.nih.gov/9811336|journal=The American Journal of Pathology|volume=153|issue=5|pages=1451–1458|doi=10.1016/S0002-9440(10)65732-X|issn=0002-9440|pmc=1853403|pmid=9811336}}</ref> This fusion is found in the majority of infantile fibrosarcoma cases. Studies have demonstrated that this fusion is sensitive to TRK inhibitors.<ref>{{Cite journal|last=Cardesa-Salzmann|first=Teresa M.|last2=Sparber-Sauer|first2=Monika|last3=Hingst|first3=Peter|last4=Erbersdobler|first4=Andreas|last5=Schneider|first5=Bjoern|last6=Hühns|first6=Maja|last7=Jakob|first7=Andre|last8=Terpe|first8=Friederike|last9=Spang|first9=Christian|date=2025-05|title=On TRacK With Larotrectinib in a Neonate With a Giant Congenital ETV6::NTRK3 Fusion-Positive Infantile Fibrosarcoma of the Head and Neck|url=https://pubmed.ncbi.nlm.nih.gov/39737858|journal=Head & Neck|volume=47|issue=5|pages=E50–E57|doi=10.1002/hed.28058|issn=1097-0347|pmc=12038221|pmid=39737858}}</ref><ref>{{Cite journal|last=Hong|first=D. S.|last2=Xu|first2=R.-H.|last3=Shen|first3=L.|last4=Dierselhuis|first4=M. P.|last5=Orbach|first5=D.|last6=McDermott|first6=R.|last7=Italiano|first7=A.|last8=Tahara|first8=M.|last9=Bernard-Gauthier|first9=V.|date=2025-06|title=Efficacy and safety of larotrectinib as first-line treatment for patients with TRK fusion cancer|url=https://pubmed.ncbi.nlm.nih.gov/40408921|journal=ESMO open|volume=10|issue=6|pages=105110|doi=10.1016/j.esmoop.2025.105110|issn=2059-7029|pmc=12151180|pmid=40408921}}</ref><ref>{{Cite journal|last=Drilon|first=Alexander|last2=Laetsch|first2=Theodore W.|last3=Kummar|first3=Shivaani|last4=DuBois|first4=Steven G.|last5=Lassen|first5=Ulrik N.|last6=Demetri|first6=George D.|last7=Nathenson|first7=Michael|last8=Doebele|first8=Robert C.|last9=Farago|first9=Anna F.|date=2018-02-22|title=Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children|url=https://pubmed.ncbi.nlm.nih.gov/29466156|journal=The New England Journal of Medicine|volume=378|issue=8|pages=731–739|doi=10.1056/NEJMoa1714448|issn=1533-4406|pmc=5857389|pmid=29466156}}</ref><ref>{{Cite journal|last=Hong|first=David S.|last2=DuBois|first2=Steven G.|last3=Kummar|first3=Shivaani|last4=Farago|first4=Anna F.|last5=Albert|first5=Catherine M.|last6=Rohrberg|first6=Kristoffer S.|last7=van Tilburg|first7=Cornelis M.|last8=Nagasubramanian|first8=Ramamoorthy|last9=Berlin|first9=Jordan D.|date=2020-04|title=Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials|url=https://pubmed.ncbi.nlm.nih.gov/32105622|journal=The Lancet. Oncology|volume=21|issue=4|pages=531–540|doi=10.1016/S1470-2045(19)30856-3|issn=1474-5488|pmc=7497841|pmid=32105622}}</ref>
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).
|-
|-
|''NTRK3''
|''NTRK3''
|''EML4''
|''EML4''
|<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''.
|In-frame fusion that is predicted to result in constitutive activation of the NTRK3 tyrosine kinase domain through autodimerization of EML4. Breakpoints typically involves exon 2 of ''EML4'' (NM_0019063.4) and exons 14 or 15 of ''NTRK3'' (NM_001243101.1).<ref name=":6" />
|None
|None
|Recurrent
|Recurrent
|D, T
|D, T
|Yes (WHO)
|Yes (WHO)
|<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).
|-
|-
|''NTRK1''
|''NTRK1''
|''LMNA, TPM3, SQSTM1, MIR584F1''
|''LMNA, TPM3, SQSTM1, MIR584F1''
|<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.
|
|None
|None
|Recurrent
|Recurrent
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|D, T
|D, T
|No
|No
|A ''SPECC1L::NTRK3'' fusion was reported in a single individual with a large infantile fibrosarcoma of the chest wall. The patient was treated with a TRK inhibitor (larotrectinib) with excellent clinical response.<ref name=":4" />
|A ''SPECC1L::NTRK3'' fusion was reported in a single individual with a large infantile fibrosarcoma of the chest wall. The patient was treated with a TRK inhibitor with excellent clinical response.<ref name=":4" />
|-
|-
|''BRAF''
|''BRAF''
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|''MET''
|''MET''
|''TFG''
|''TFG''
|In-frame fusion that is predicted to result in constitutive action of the MET tyrosine kinase domain through dimerization of the TFG dimerization domains. In this case, the breakpoint was in exon 7 of ''TFG'' and exon 15 of ''MET'' and encompassed the entire tyrosine kinase domain of MET.<ref name=":5">{{Cite journal|last=Flucke|first=Uta|last2=van Noesel|first2=Max M.|last3=Wijnen|first3=Marc|last4=Zhang|first4=Lei|last5=Chen|first5=Chun-Liang|last6=Sung|first6=Yun-Shao|last7=Antonescu|first7=Cristina R.|date=2017-09|title=TFG-MET fusion in an infantile spindle cell sarcoma with neural features|url=https://pubmed.ncbi.nlm.nih.gov/28510278|journal=Genes, Chromosomes & Cancer|volume=56|issue=9|pages=663–667|doi=10.1002/gcc.22470|issn=1098-2264|pmc=5507719|pmid=28510278}}</ref>  
|In-frame fusion that is predicted to result in constitutive action of the MET tyrosine kinase domain through dimerization of the TFG dimerization domains. In this case, the breakpoint was in exon 7 of ''TFG'' and exon 15 of ''MET'' and encompassed the entire tyrosine kinase domain of MET.<ref name=":5">{{Cite journal|last=Flucke|first=Uta|last2=van Noesel|first2=Max M.|last3=Wijnen|first3=Marc|last4=Zhang|first4=Lei|last5=Chen|first5=Chun-Liang|last6=Sung|first6=Yun-Shao|last7=Antonescu|first7=Cristina R.|date=2017-09|title=TFG-MET fusion in an infantile spindle cell sarcoma with neural features|url=https://pubmed.ncbi.nlm.nih.gov/28510278|journal=Genes, Chromosomes & Cancer|volume=56|issue=9|pages=663–667|doi=10.1002/gcc.22470|issn=1098-2264|pmc=5507719|pmid=28510278}}</ref>
|None
|None
|Rare
|Rare
|D
|D
|Yes (WHO)
|Yes (WHO)
|A ''TFG::MET'' fusion was reported in a single individual with an unusual infantile spindle cell sarcoma that morphologically resembled infantile fibrosarcoma. MET IHC showed diffuse expression with moderate intensity and RNA expression analysis indicated an intermediate overexpression of ''MET''.<ref name=":5" />  
|A ''TFG::MET'' fusion was reported in a single individual with an unusual infantile spindle cell sarcoma that morphologically resembled infantile fibrosarcoma. MET IHC showed diffuse expression with moderate intensity and RNA expression analysis indicated an intermediate overexpression of ''MET''.<ref name=":5" />
|}
|}
==Individual Region Genomic Gain/Loss/LOH==
==Individual Region Genomic Gain/Loss/LOH==
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***Provides an unbiased approach to fusion calling
***Provides an unbiased approach to fusion calling
*Fluorescence ''in situ'' hybridization (FISH)
*Fluorescence ''in situ'' hybridization (FISH)
**Break apart probes for ''ETV6'' and/or ''NTRK3'' will identify a rearrangement (''ETV6::NTRK3'') present in the majority of infantile fibrosarcoma. Consider other fusion partners is ''ETV6'' FISH is negative.  
**Break apart probes for ''ETV6'' and/or ''NTRK3'' will identify a rearrangement (''ETV6::NTRK3'') present in the majority of infantile fibrosarcoma. Consider other fusion partners is ''ETV6'' FISH is negative.
*Karyotyping
*Karyotyping
**Can identify the t(12;15) rearrangement as well as other commonly reported aneusomies (i.e. whole chromosome gains of 8, 11, 17, 20)
**Can identify the t(12;15) rearrangement as well as other commonly reported aneusomies (i.e. whole chromosome gains of 8, 11, 17, 20)
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