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

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

Research output: Contribution to journalArticlepeer-review

19 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 2012
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Fingerprint Dive into the research topics of 'Mediators of receptor tyrosine kinase activation in infantile fibrosarcoma: A Children's Oncology Group study'. Together they form a unique fingerprint.

Cite this