Mediators of receptor tyrosine kinase activation in infantile fibrosarcoma: a Children's Oncology Group study

J Pathol. 2012 Sep;228(1):119-30. doi: 10.1002/path.4010. Epub 2012 Jul 2.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Biomarkers, Tumor / metabolism
  • DNA, Neoplasm / analysis
  • ETS Translocation Variant 6 Protein
  • Gene Expression Regulation, Neoplastic / physiology
  • Humans
  • In Situ Hybridization, Fluorescence
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / metabolism
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Nephroma, Mesoblastic / genetics*
  • Nephroma, Mesoblastic / metabolism
  • Oncogene Proteins, Fusion / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-ets / genetics
  • Proto-Oncogene Proteins c-ets / metabolism
  • Proto-Oncogene Proteins pp60(c-src) / metabolism
  • Receptor, trkC / genetics
  • Receptor, trkC / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism

Substances

  • Biomarkers, Tumor
  • DNA, Neoplasm
  • ETV6-NTRK3 fusion protein, human
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Proteins c-ets
  • Repressor Proteins
  • Phosphatidylinositol 3-Kinases
  • Receptor, trkC
  • Proto-Oncogene Proteins pp60(c-src)
  • Mitogen-Activated Protein Kinase Kinases

Associated data

  • GEO/GSE30946