Molecular characterization of pediatric gastrointestinal stromal tumors Journal Article


Authors: Agaram, N. P.; LaQuaglia, M. P.; Ustun, B.; Guo, T.; Wong, G. C.; Socci, N. D.; Maki, R. G.; DeMatteo, R. P.; Besmer, P.; Antonescu, C. R.
Article Title: Molecular characterization of pediatric gastrointestinal stromal tumors
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. © 2008 American Association for Cancer Research.
Keywords: adolescent; child; clinical article; school child; gene mutation; genetics; mutation; histopathology; sorafenib; sunitinib; antineoplastic agents; antineoplastic agent; cell proliferation; gene; in situ hybridization, fluorescence; gastrointestinal stromal tumor; imatinib; platelet derived growth factor alpha receptor; stem cell factor; stem cell factor receptor; gene overexpression; gastrointestinal stromal tumors; proto-oncogene proteins c-kit; receptor, platelet-derived growth factor alpha; reverse transcription polymerase chain reaction; apoptosis; gene expression; gene expression profiling; protein kinase inhibitor; epidermal growth factor receptor; genotype; drug effect; pathology; dasatinib; protein kinase inhibitors; blotting, western; fluorescence in situ hybridization; reverse transcriptase polymerase chain reaction; nucleotide sequence; western blotting; immunoprecipitation; sex difference; real time polymerase chain reaction; dna mutational analysis; gene dosage; sex factors; nilotinib; ic 50; b raf kinase; kit gene; baalc gene; fgf4 gene; igf1r gene; nell1 gene; pdgfra gene; plag1 gene
Journal Title: Clinical Cancer Research
Volume: 14
Issue: 10
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2008-05-15
Start Page: 3204
End Page: 3215
Language: English
DOI: 10.1158/1078-0432.ccr-07-1984
PUBMED: 18483389
PROVIDER: scopus
PMCID: PMC3805121
DOI/URL:
Notes: --- - "Cited By (since 1996): 66" - "Export Date: 17 November 2011" - "CODEN: CCREF" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Ronald P DeMatteo
    597 DeMatteo
  2. Narasimhan P Agaram
    117 Agaram
  3. Cristina R Antonescu
    606 Antonescu
  4. Robert Maki
    211 Maki
  5. Nicholas D Socci
    182 Socci
  6. Tianhua Guo
    22 Guo
  7. Peter Besmer
    81 Besmer
  8. Grace C Wong
    11 Wong
  9. Berrin Ustun
    1 Ustun