Data from Novel Oncogenic <i>PDGFRA</i> Mutations in Pediatric High-Grade Gliomas

Abstract

<div>Abstract<p>The outcome for children with high-grade gliomas (HGG) remains dismal, with a 2-year survival rate of only 10% to 30%. Diffuse intrinsic pontine glioma (DIPG) comprise a subset of HGG that arise in the brainstem almost exclusively in children. Genome-wide analyses of copy number imbalances previously showed that platelet-derived growth factor receptor α (<i>PDGFRA</i>) is the most frequent target of focal amplification in pediatric HGGs, including DIPGs. To determine whether <i>PDGFRA</i> is also targeted by more subtle mutations missed by copy number analysis, we sequenced all <i>PDGFRA</i> coding exons from a cohort of pediatric HGGs. Somatic-activating mutations were identified in 14.4% (13 of 90) of nonbrainstem pediatric HGGs and 4.7% (2 of 43) of DIPGs, including missense mutations and in-frame deletions and insertions not previously described. Forty percent of tumors with mutation showed concurrent amplification, whereas 60% carried heterozygous mutations. Six different mutations impacting different domains all resulted in ligand-independent receptor activation that was blocked by small molecule inhibitors of PDGFR. Expression of mutants in p53-null primary mouse astrocytes conferred a proliferative advantage <i>in vitro</i> and generated HGGs <i>in vivo</i> with complete penetrance when implanted into brain. The gene expression signatures of these murine HGGs reflected the spectrum of human diffuse HGGs. <i>PDGFRA</i> intragenic deletion of exons 8 and 9 were previously shown in adult HGG, but were not detected in 83 nonbrainstem pediatric HGG and 57 DIPGs. Thus, a distinct spectrum of mutations confers constitutive receptor activation and oncogenic activity to PDGFRα in childhood HGG. <i>Cancer Res; 73(20); 6219–29. ©2013 AACR</i>.</p></div>