title: Mediators of receptor tyrosine kinase activation in infantile fibrosarcoma: a Children's Oncology Group study.
abstract: Infantile fibrosarcoma (IFS; also known as cellular congenital mesoblastic nephroma, CMN, when in the kidney) is a rare, undifferentiated tumour often characterized by the ETV6-NTRK3 fusion transcript. Our goal was to identify downstream pathways, diagnostic markers and potential therapeutic targets for IFS/CMN. Global gene expression, reverse-phase protein array and ETV6-NTRK3 fusion analyses were performed on 14 IFS/CMN and compared with 41 other paediatric renal tumours. These analyses confirm significant receptor tyrosine kinase (RTK) activation, with evidence of PI3-Akt, MAPK and SRC activation. In particular, GAB2 docking protein, STAT5-pTyr-694, STAT3-pSer-729 and YAP-pSer-127 were elevated, and TAZ-pSer-89 was decreased. This provides mRNA and proteomic evidence that GAB2, STAT activation and phosphorylation of the Hippo pathway transcription co-activators YAP and TAZ contribute to the RTK signal transduction in IFS/CMN. All IFS/CMN tumours displayed a distinctive gene expression pattern that may be diagnostically useful. Unexpectedly, abundant ETV6-NTRK3 transcript copies were present in only 7/14 IFS, with very low copy number in 3/14. An additional 4/14 were negative by RT-PCR and absence of ETV6-NTRK3 was confirmed by FISH for both ETV6 and NTRK3. Therefore, molecular mechanisms other than ETV6-NTRK3 fusion are responsible for the development of some IFS/CMNs and the absence of ETV6-NTRK3 fusion products should not exclude IFS/CMN as a diagnosis.
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine and the Robert H Lurie Comprehensive Cancer Center, Chicago, IL, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Gadd
authors.forename: Patricia
authors.initials: P
authors.lastname: Beezhold
authors.forename: Lawrence
authors.initials: L
authors.lastname: Jennings
authors.forename: David
authors.initials: D
authors.lastname: George
authors.forename: Katrin
authors.initials: K
authors.lastname: Leuer
authors.forename: Chiang-Ching
authors.initials: CC
authors.lastname: Huang
authors.forename: Vicki
authors.initials: V
authors.lastname: Huff
authors.forename: Cristina
authors.initials: C
authors.lastname: Tognon
authors.forename: Poul H B
authors.initials: PH
authors.lastname: Sorensen
authors.forename: Timothy
authors.initials: T
authors.lastname: Triche
authors.forename: Cheryl M
authors.initials: CM
authors.lastname: Coffin
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Perlman
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D004273:DNA, Neoplasm / Q000032:analysis; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D018201:Nephroma, Mesoblastic / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D020812:Receptor, trkC / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D020929:Mitogen-Activated Protein Kinase Kinases; D015514:Oncogene Proteins, Fusion; D019869:Phosphatidylinositol 3-Kinases; D050783:Proto-Oncogene Proteins c-ets; D016392:Proto-Oncogene Proteins pp60(c-src); D020812:Receptor, trkC; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein; C484319:ETV6-NTRK3 fusion protein, human