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

Samantha L Gadd, Patricia Beezhold, Lawrence J Jennings, David George, Katrin Carlson, Chiang Ching Huang, Vicki Huff, Cristina Tognon, Poul H.B. Sorensen, Timothy Triche, Cheryl M. Coffin, Elizabeth J Perlman*

*Corresponding author for this work

Research output: Contribution to journalArticle

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)119-130
Number of pages12
JournalJournal of Pathology
Volume228
Issue number1
DOIs
StatePublished - Sep 1 2012

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Keywords

  • ETV6-NTRK3
  • GAB2
  • Hippo
  • congenital fibrosarcoma
  • infantile fibrosarcoma
  • mesoblastic nephroma

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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