Abstract
Fewer than 15% of gastrointestinal stromal tumors (GIST) in pediatric patients harbor KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutations in contrast to a mutation rate of 80% in adult GISTs. However, some therapeutic inhibitors of KIT have efficacy in pediatric GIST, suggesting that KIT may, nevertheless, play an important role in oncogenesis. In adult GIST, characteristic cytogenetic changes occur during progression to malignancy. A better understanding of mechanisms of genetic progression and KIT and PDGFRA transforming roles in pediatric GIST might facilitate treatment advances. KIT and PDGFRA mutation analysis was done in 27 pediatric GISTs. The activation status of KIT, PDGFRA, and downstream signaling intermediates was defined, and chromosomal aberrations were determined by single nucleotide polymorphism assays. Mutations in KIT or PDGFRA were identified in 11% of pediatric GISTs. KIT and the signaling intermediates AKT and mitogen-activated protein kinase were activated in pediatric GISTs. In particular, most pediatric KIT-wild-type GISTs displayed levels of KIT activation similar to levels in adult KIT-mutant GISTs. Pediatric KIT-wild-type GISTs lacked the typical cytogenetic deletions seen in adult KIT-mutant GISTs. Notably, most pediatric KIT-wild-type GISTs progress to malignancy without acquiring large-scale chromosomal aberrations, which is a phenomenon not reported previously in malignant solid tumors. KIT activation levels in pediatric KIT-wild-type GISTs are comparable with those in KIT-mutant GISTs. Therapies that inhibit KIT activation, or crucial KIT signaling intermediates, should be explored in pediatric KIT-wild-type GIST.
Highlights
Gastrointestinal stromal tumor (GIST) is a neoplasm of mesenchymal origin in the gastrointestinal tract of adults and children.A key, early transforming event in 80% of adult GISTs is mutation, leading to ligand-independent activation of KIT or, less commonly, platelet-derived growth factor receptor a (PDGFRA; ref. 1)
In adult GIST, oncogenic KIT or platelet-derived growth factor receptor A (PDGFRA) mutations are likely sufficient for transformation, but progression from benign to malignant GIST is characterized by sequential acquisition of chromosomal deletions at 14q, 22q, 1p, and 9p [1]
Three of twenty-seven GISTs (11%) had KIT or PDGFRA mutations that included a homozygous KIT exon 11 mutation, resulting in deletion VV559-560, a heterozygous KIT exon 9 mutation resulting in AY502503 insertion, and a heterozygous PDGFRA exon 18 mutation resulting in D842V substitution
Summary
Gastrointestinal stromal tumor (GIST) is a neoplasm of mesenchymal origin in the gastrointestinal tract of adults and children.A key, early transforming event in 80% of adult GISTs is mutation, leading to ligand-independent activation of KIT or, less commonly, platelet-derived growth factor receptor a (PDGFRA; ref. 1). Whereas pediatric GIST expresses KIT at levels comparable with adult GIST, only 15% of the pediatric tumors harbor activating mutations in KIT or PDGFRA [2]. We find that most pediatric KIT–wild-type GISTs have KIT activation at levels comparable with KIT-mutant GISTs. Together with the therapeutic responses to sunitinib, these findings suggest that KIT, lacking mutations, might provide an important transforming mechanism in pediatric GIST.
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