Data from Pediatric <i>KIT</i>–Wild-Type and Platelet-Derived Growth Factor Receptor α–Wild-Type Gastrointestinal Stromal Tumors Share KIT Activation but not Mechanisms of Genetic Progression with Adult Gastrointestinal Stromal Tumors

Abstract

<div>Abstract<p>Fewer than 15% of gastrointestinal stromal tumors (GIST) in pediatric patients harbor <i>KIT</i> or platelet-derived growth factor receptor α (<i>PDGFRA</i>) 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. <i>KIT</i> and <i>PDGFRA</i> 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 <i>KIT</i> or <i>PDGFRA</i> 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 <i>KIT</i>–wild-type GISTs displayed levels of KIT activation similar to levels in adult <i>KIT</i>-mutant GISTs. Pediatric <i>KIT</i>–wild-type GISTs lacked the typical cytogenetic deletions seen in adult <i>KIT</i>-mutant GISTs. Notably, most pediatric <i>KIT</i>–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 <i>KIT</i>–wild-type GISTs are comparable with those in <i>KIT</i>-mutant GISTs. Therapies that inhibit KIT activation, or crucial KIT signaling intermediates, should be explored in pediatric <i>KIT</i>–wild-type GIST. [Cancer Res 2007;67(19):9084–8]</p></div>