STBT5:Infantile fibrosarcoma: Difference between revisions

|''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.<ref name=":1">{{Cite journal|last=Aepala|first=Megha R.|last2=Peiris|first2=Malalage N.|last3=Jiang|first3=Zian|last4=Yang|first4=Wei|last5=Meyer|first5=April N.|last6=Donoghue|first6=Daniel J.|date=2022-12|title=Nefarious NTRK oncogenic fusions in pediatric sarcomas: Too many to Trk|url=https://pubmed.ncbi.nlm.nih.gov/36153202|journal=Cytokine & Growth Factor Reviews|volume=68|pages=93–106|doi=10.1016/j.cytogfr.2022.08.003|issn=1879-0305|pmid=36153202}}</ref> Breakpoints typically involve 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)

|The ''ETV6::NTRK3'' fusion [t(12;15)] is diagnostic of infantile fibrosarcoma in the appropriate morphology and clinical context.<ref name=":6" /><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 name=":3">{{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 name=":7">{{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 name=":8">{{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 name=":9">{{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 name=":10">{{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><ref name=":11">{{Cite journal|last=Laetsch|first=Theodore W.|last2=Voss|first2=Stephan|last3=Ludwig|first3=Kathleen|last4=Hall|first4=David|last5=Barkauskas|first5=Donald A.|last6=DuBois|first6=Steven G.|last7=Ronan|first7=Joan|last8=Rudzinski|first8=Erin R.|last9=Memken|first9=Amanda|date=2025-04|title=Larotrectinib for Newly Diagnosed Infantile Fibrosarcoma and Other Pediatric NTRK Fusion-Positive Solid Tumors (Children's Oncology Group ADVL1823)|url=https://pubmed.ncbi.nlm.nih.gov/39652801|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=43|issue=10|pages=1188–1197|doi=10.1200/JCO-24-01854|issn=1527-7755|pmc=11954674|pmid=39652801}}</ref>

|In-frame fusion that is predicted to result in constitutive activation of the NTRK3 tyrosine kinase domain through autodimerization of EML4.<ref name=":1" /> Breakpoints typically involve exon 2 of ''EML4'' (NM_0019063.4) and exons 14 of ''NTRK3'' (NM_001243101.1).<ref name=":6" />

|The ''EML4::NTRK3'' fusion is diagnostic of infantile fibrosarcoma in the appropriate morphology and clinical context.<ref name=":6" /><ref name=":3" /><ref name=":2">{{Cite journal|last=Davis|first=Jessica L.|last2=Lockwood|first2=Christina M.|last3=Albert|first3=Catherine M.|last4=Tsuchiya|first4=Karen|last5=Hawkins|first5=Douglas S.|last6=Rudzinski|first6=Erin R.|date=2018|title=Infantile NTRK-associated Mesenchymal Tumors|url=https://pubmed.ncbi.nlm.nih.gov/28683589|journal=Pediatric and Developmental Pathology: The Official Journal of the Society for Pediatric Pathology and the Paediatric Pathology Society|volume=21|issue=1|pages=68–78|doi=10.1177/1093526617712639|issn=1093-5266|pmid=28683589}}</ref><ref name=":12">{{Cite journal|last=Kao|first=Yu-Chien|last2=Fletcher|first2=Christopher D. M.|last3=Alaggio|first3=Rita|last4=Wexler|first4=Leonard|last5=Zhang|first5=Lei|last6=Sung|first6=Yun-Shao|last7=Orhan|first7=Dicle|last8=Chang|first8=Wei-Chin|last9=Swanson|first9=David|date=2018-01|title=Recurrent BRAF Gene Fusions in a Subset of Pediatric Spindle Cell Sarcomas: Expanding the Genetic Spectrum of Tumors With Overlapping Features With Infantile Fibrosarcoma|url=https://pubmed.ncbi.nlm.nih.gov/28877062|journal=The American Journal of Surgical Pathology|volume=42|issue=1|pages=28–38|doi=10.1097/PAS.0000000000000938|issn=1532-0979|pmc=5730460|pmid=28877062}}</ref> Studies have demonstrated that this fusion is sensitive to TRK inhibitors.<ref name=":8" /><ref name=":10" /><ref name=":11" />

|In-frame fusion that is predicted to result in constitutive activation of the NTRK1 tyrosine kinase domain likely through dimerization of the 5' fusion partner.<ref name=":1" />

|''NTRK1'' fusions may be diagnostic of infantile fibrosarcoma in the appropriate morphology and clinical context.<ref name=":2" /><ref name=":12" /><ref>{{Cite journal|last=Pavlick|first=Dean|last2=Schrock|first2=Alexa B.|last3=Malicki|first3=Denise|last4=Stephens|first4=Philip J.|last5=Kuo|first5=Dennis J.|last6=Ahn|first6=Hyunah|last7=Turpin|first7=Brian|last8=Allen|first8=Justin M.|last9=Rosenzweig|first9=Mark|date=2017-08|title=Identification of NTRK fusions in pediatric mesenchymal tumors|url=https://pubmed.ncbi.nlm.nih.gov/28097808|journal=Pediatric Blood & Cancer|volume=64|issue=8|doi=10.1002/pbc.26433|issn=1545-5017|pmid=28097808}}</ref> Studies have demonstrated that NTRK1 fusions are sensitive to TRK inhibitors.<ref name=":8" /><ref name=":9" /><ref name=":10" /><ref name=":11" />

|Intragenic gene rearrangement that is predicted to result in a constitutively active form of BRAF due to loss of the negative regulatory Ras-binding domain.<ref name=":3" />

|Whole chromosome gain of 8 is commonly observed in infantile fibrosarcoma.<ref name=":6" /><ref name=":7" /><ref name=":2" /><ref name=":0">{{Cite journal|last=Sandberg|first=Avery A.|last2=Bridge|first2=Julia A.|date=2002-01-01|title=Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: congenital (infantile) fibrosarcoma and mesoblastic nephroma|url=https://pubmed.ncbi.nlm.nih.gov/11801301|journal=Cancer Genetics and Cytogenetics|volume=132|issue=1|pages=1–13|doi=10.1016/s0165-4608(01)00528-3|issn=0165-4608|pmid=11801301}}</ref>

|Whole chromosome gain of 11 is commonly observed in infantile fibrosarcoma.<ref name=":6" /><ref name=":7" /><ref name=":2" /><ref name=":0" />

|Whole chromosome gain of 17 is commonly observed in infantile fibrosarcoma.<ref name=":6" /><ref name=":7" /><ref name=":2" /><ref name=":0" />

|Whole chromosome gain of 20 is commonly observed in infantile fibrosarcoma.<ref name=":6" /><ref name=":7" /><ref name=":2" /><ref name=":0" />

|''NTRK1/2/3''; Activating fusion

|RAS/MAPK signaling

|Increased cell growth and proliferation

*DNA sequencing

**Currently, there are no recurrently described somatic SNV/indels for infantile fibrosarcoma