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

14 Citations (Scopus)

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

Fingerprint

Fibrosarcoma
Receptor Protein-Tyrosine Kinases
Mesoblastic Nephroma
STAT5 Transcription Factor
Kidney
Gene Expression
Neoplasms
Protein Array Analysis
Proteomics
Signal Transduction
Phosphorylation
Pediatrics
Polymerase Chain Reaction
Messenger RNA
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Gadd, Samantha L ; Beezhold, Patricia ; Jennings, Lawrence J ; George, David ; Carlson, Katrin ; Huang, Chiang Ching ; Huff, Vicki ; Tognon, Cristina ; Sorensen, Poul H.B. ; Triche, Timothy ; Coffin, Cheryl M. ; Perlman, Elizabeth J. / Mediators of receptor tyrosine kinase activation in infantile fibrosarcoma : A Children's Oncology Group study. In: Journal of Pathology. 2012 ; Vol. 228, No. 1. pp. 119-130.
@article{64844f32423c4cb999c0f5ad576ace22,
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.",
keywords = "ETV6-NTRK3, GAB2, Hippo, congenital fibrosarcoma, infantile fibrosarcoma, mesoblastic nephroma",
author = "Gadd, {Samantha L} and Patricia Beezhold and Jennings, {Lawrence J} and David George and Katrin Carlson and Huang, {Chiang Ching} and Vicki Huff and Cristina Tognon and Sorensen, {Poul H.B.} and Timothy Triche and Coffin, {Cheryl M.} and Perlman, {Elizabeth J}",
year = "2012",
month = "9",
day = "1",
doi = "10.1002/path.4010",
language = "English (US)",
volume = "228",
pages = "119--130",
journal = "Journal of Pathology",
issn = "0022-3417",
publisher = "John Wiley and Sons Ltd",
number = "1",

}

Mediators of receptor tyrosine kinase activation in infantile fibrosarcoma : A Children's Oncology Group study. / Gadd, Samantha L; Beezhold, Patricia; Jennings, Lawrence J; George, David; Carlson, Katrin; Huang, Chiang Ching; Huff, Vicki; Tognon, Cristina; Sorensen, Poul H.B.; Triche, Timothy; Coffin, Cheryl M.; Perlman, Elizabeth J.

In: Journal of Pathology, Vol. 228, No. 1, 01.09.2012, p. 119-130.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mediators of receptor tyrosine kinase activation in infantile fibrosarcoma

T2 - A Children's Oncology Group study

AU - Gadd, Samantha L

AU - Beezhold, Patricia

AU - Jennings, Lawrence J

AU - George, David

AU - Carlson, Katrin

AU - Huang, Chiang Ching

AU - Huff, Vicki

AU - Tognon, Cristina

AU - Sorensen, Poul H.B.

AU - Triche, Timothy

AU - Coffin, Cheryl M.

AU - Perlman, Elizabeth J

PY - 2012/9/1

Y1 - 2012/9/1

N2 - 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.

AB - 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.

KW - ETV6-NTRK3

KW - GAB2

KW - Hippo

KW - congenital fibrosarcoma

KW - infantile fibrosarcoma

KW - mesoblastic nephroma

UR - http://www.scopus.com/inward/record.url?scp=84864757485&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84864757485&partnerID=8YFLogxK

U2 - 10.1002/path.4010

DO - 10.1002/path.4010

M3 - Article

C2 - 22374738

AN - SCOPUS:84864757485

VL - 228

SP - 119

EP - 130

JO - Journal of Pathology

JF - Journal of Pathology

SN - 0022-3417

IS - 1

ER -