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Updated: Jul 5, 2026
Molecular and Immunologic Techniques in a Genetically Engineered Mouse Model of Gastrointestinal Stromal Tumor
Published on: May 2, 2022
Molecular characterization of pediatric gastrointestinal stromal tumors
Narasimhan P Agaram1, Michael P Laquaglia, Berrin Ustun
1Department of Pathology, Sloan-Kettering Institute, New York, New York 10021, USA.
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.
Insights
Pediatric gastrointestinal stromal tumors (GIST) are rare and distinct from adult GIST. Second-generation kinase inhibitors show promise for treating pediatric GIST lacking KIT/PDGFRA mutations.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Pediatric gastrointestinal stromal tumors (GIST) are rare, multifocal gastric tumors predominantly affecting females.
- These tumors typically lack mutations in KIT and PDGFRA but consistently overexpress KIT oncoprotein.
Purpose of the Study:
- Investigate KIT downstream target activation and KIT/PDGFRA gene copy number alterations in pediatric GIST.
- Identify novel therapeutic targets through gene expression profiling.
- Evaluate tyrosine kinase receptor activation using proteomic profiling.
Main Methods:
- Analyzed KIT/PDGFRA genotype and KIT downstream target activation in 17 pediatric GISTs.
- Compared transcriptional profiles of pediatric GISTs with adult wild-type (WT) GISTs.
- Assessed sensitivity of WT KIT-expressing cells and GIST explants to kinase inhibitors.
Main Results:
- All female patients had a KIT/PDGFRA WT genotype; two males had KIT or PDGFRA mutations.
- KIT downstream targets were consistently activated in pediatric GIST.
- Pediatric GISTs exhibit a unique transcriptional signature, including overexpression of BAALC, PLAG1, IGF1R, FGF4, and NELL1.
- Nilotinib, sunitinib, dasatinib, and sorafenib demonstrated superior efficacy over imatinib against WT KIT in vitro.
Conclusions:
- Pediatric GIST can occur in males with activating KIT/PDGFRA mutations, indicating varied biology compared to adult WT GIST.
- Distinct transcriptional profiles suggest unique molecular pathways in pediatric GIST.
- Second-generation kinase inhibitors show potential for improved clinical benefit in pediatric GIST.
