Molecular characterization of pediatric gastrointestinal stromal tumors

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. (May 2008) Molecular characterization of pediatric gastrointestinal stromal tumors. Clin Cancer Res, 14 (10). pp. 3204-15. ISSN 1078-0432 (Print)1078-0432 (Linking)

DOI: 10.1158/1078-0432.CCR-07-1984


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.

Item Type: Paper
Uncontrolled Keywords: Adolescent Antineoplastic Agents/pharmacology Apoptosis/drug effects Blotting, Western Cell Proliferation/drug effects Child DNA Mutational Analysis Female Gastrointestinal Stromal Tumors/*genetics/pathology Gene Dosage Gene Expression *Gene Expression Profiling Humans Immunoprecipitation In Situ Hybridization, Fluorescence Male Mutation Protein Kinase Inhibitors/pharmacology Proto-Oncogene Proteins c-kit/*genetics Receptor, Platelet-Derived Growth Factor alpha/*genetics Reverse Transcriptase Polymerase Chain Reaction Sex Factors
Subjects: organism description > animal > developmental stage > child
diseases & disorders > cancer > cancer types > gastrointestinal stromal tumors
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression
CSHL Authors:
Communities: CSHL labs > Maki lab
Depositing User: Matt Covey
Date: 15 May 2008
Date Deposited: 26 Oct 2016 16:59
Last Modified: 26 Oct 2016 16:59
PMCID: PMC3805121
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