Molecular characterization of pediatric gastrointestinal stromal tumors

Narasimhan P. Agaram, Michael P. Laquaglia, Berrin Ustun, Tianhua Guo, Grace C.wong, Nicholas D. Socci, Robert G. Maki, Ronald P. Dematteo, Peter Besmer, Cristina R. Antonescu

Research output: Contribution to journalArticle

191 Citations (Scopus)

Abstract

Purpose: Pediatric gastrointestinal stromal tumors (GIST) are rare and occur preferentially in females as multifocal gastric tumors, typically lacking mutations in KIT and PDGFRA. As KIT oncoprotein is consistently overexpressed in pediatric GIST, we sought to investigate the activation of KIT downstream targets and alterations of KIT/PDGFRA gene copy number, mine novel therapeutic targets by gene expression, and test tyrosine kinase receptor activation by proteomic profiling. Experimental Design: Seventeen pediatric GISTs were investigated for KIT/PDGFRA genotype and biochemical activation of KIT downstream targets. The transcriptional profile of 13 nodules from 8 pediatric patients was compared with 8 adult wild-type (WT) GISTs, including 3 young adults. The drug sensitivity of second-generation kinase inhibitors was tested in murine Ba/F3 cells expressing human WT KIT, as well as in short-term culture of explants of WT GIST cells. Results: A KIT/PDGFRA WT genotype was identified in all 12 female patients, whereas two of five males had either a KIT exon 11 or PDGFRA exon 18 mutation. KIT downstream targets were consistently activated. Pediatric GISTs showed a distinct transcriptional signature, with overexpression of BAALC. PLAG1, IGF1R, FGF4, and NELL1. In vitro studies showed that nilotinib, sunitinib, dasatinib, and sorafenib are more effective than imatinib against WT KIT. Conclusions: Rare cases of pediatric GIST may occur in male patients and harbor activating KIT/PDGFRA mutations. Pediatric GISTs show distinct transcriptional signature, suggesting a different biology than WT GIST in adults. In vitro drug screening showed that second-generation kinase inhibitors may provide greater clinical benefit in pediatric GIST.

Original languageEnglish (US)
Pages (from-to)3204-3215
Number of pages12
JournalClinical Cancer Research
Volume14
Issue number10
DOIs
StatePublished - May 15 2008
Externally publishedYes

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Gastrointestinal Stromal Tumors
Pediatrics
Mutation
Exons
Phosphotransferases
Genotype
Preclinical Drug Evaluations
Gene Dosage
Oncogene Proteins
Receptor Protein-Tyrosine Kinases
Stromal Cells
Proteomics
Young Adult
Stomach
Research Design
Gene Expression

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Agaram, N. P., Laquaglia, M. P., Ustun, B., Guo, T., C.wong, G., Socci, N. D., ... Antonescu, C. R. (2008). Molecular characterization of pediatric gastrointestinal stromal tumors. Clinical Cancer Research, 14(10), 3204-3215. https://doi.org/10.1158/1078-0432.CCR-07-1984

Molecular characterization of pediatric gastrointestinal stromal tumors. / Agaram, Narasimhan P.; Laquaglia, Michael P.; Ustun, Berrin; Guo, Tianhua; C.wong, Grace; Socci, Nicholas D.; Maki, Robert G.; Dematteo, Ronald P.; Besmer, Peter; Antonescu, Cristina R.

In: Clinical Cancer Research, Vol. 14, No. 10, 15.05.2008, p. 3204-3215.

Research output: Contribution to journalArticle

Agaram, NP, Laquaglia, MP, Ustun, B, Guo, T, C.wong, G, Socci, ND, Maki, RG, Dematteo, RP, Besmer, P & Antonescu, CR 2008, 'Molecular characterization of pediatric gastrointestinal stromal tumors', Clinical Cancer Research, vol. 14, no. 10, pp. 3204-3215. https://doi.org/10.1158/1078-0432.CCR-07-1984
Agaram, Narasimhan P. ; Laquaglia, Michael P. ; Ustun, Berrin ; Guo, Tianhua ; C.wong, Grace ; Socci, Nicholas D. ; Maki, Robert G. ; Dematteo, Ronald P. ; Besmer, Peter ; Antonescu, Cristina R. / Molecular characterization of pediatric gastrointestinal stromal tumors. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 10. pp. 3204-3215.
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AU - Agaram, Narasimhan P.

AU - Laquaglia, Michael P.

AU - Ustun, Berrin

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AU - C.wong, Grace

AU - Socci, Nicholas D.

AU - Maki, Robert G.

AU - Dematteo, Ronald P.

AU - Besmer, Peter

AU - Antonescu, Cristina R.

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N2 - Purpose: Pediatric gastrointestinal stromal tumors (GIST) are rare and occur preferentially in females as multifocal gastric tumors, typically lacking mutations in KIT and PDGFRA. As KIT oncoprotein is consistently overexpressed in pediatric GIST, we sought to investigate the activation of KIT downstream targets and alterations of KIT/PDGFRA gene copy number, mine novel therapeutic targets by gene expression, and test tyrosine kinase receptor activation by proteomic profiling. Experimental Design: Seventeen pediatric GISTs were investigated for KIT/PDGFRA genotype and biochemical activation of KIT downstream targets. The transcriptional profile of 13 nodules from 8 pediatric patients was compared with 8 adult wild-type (WT) GISTs, including 3 young adults. The drug sensitivity of second-generation kinase inhibitors was tested in murine Ba/F3 cells expressing human WT KIT, as well as in short-term culture of explants of WT GIST cells. Results: A KIT/PDGFRA WT genotype was identified in all 12 female patients, whereas two of five males had either a KIT exon 11 or PDGFRA exon 18 mutation. KIT downstream targets were consistently activated. Pediatric GISTs showed a distinct transcriptional signature, with overexpression of BAALC. PLAG1, IGF1R, FGF4, and NELL1. In vitro studies showed that nilotinib, sunitinib, dasatinib, and sorafenib are more effective than imatinib against WT KIT. Conclusions: Rare cases of pediatric GIST may occur in male patients and harbor activating KIT/PDGFRA mutations. Pediatric GISTs show distinct transcriptional signature, suggesting a different biology than WT GIST in adults. In vitro drug screening showed that second-generation kinase inhibitors may provide greater clinical benefit in pediatric GIST.

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