Novel Oncogenic PDGFRA Mutations in Pediatric High-Grade Gliomas

Abstract

The outcome for children with high-grade gliomas (HGG) remains dismal, with a two-year survival rate of only 10–30%. Diffuse intrinsic pontine glioma (DIPG) comprise a subset of HGG that arise in brainstem almost exclusively in children. Genome-wide analyses of copy number imbalances previously showed that platelet derived growth factor receptor alpha (PDGFRA) is the most frequent target of focal amplification in pediatric HGGs, including DIPGs. To determine whether PDGFRA is also targeted by more subtle mutations missed by copy number analysis, we sequenced all PDGFRA coding exons from a cohort of pediatric HGGs. Somatic activating mutations were identified in 14.4% (13/90) of non-brainstem pediatric HGGs and 4.7% (2/43) of DIPGs, including missense mutations and in-frame deletions and insertions not previously described. 40% of tumors with mutation showed concurrent amplification, while 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 in vitro, and generated HGGs in vivo with complete penetrance when implanted into brain. The gene expression signatures of these murine HGGs reflected the spectrum of human diffuse HGGs. PDGFRA intragenic deletion of exons 8 and 9 were previously shown in adult HGG, but were not detected in 83 non-brainstem pediatric HGG and 57 DIPGs. Thus, a distinct spectrum of mutations confers constitutive receptor activation and oncogenic activity to PDGFRα in childhood HGG.

Molecular mechanisms and therapeutic targets in pediatric brain tumors

“…Initially, these were found to resemble the receptor tyrosine kinase I (RTKI) subgroup, which is enriched for genomic alterations of platelet-derived growth factor receptor a (PDGFRA), but there is growing evidence for the need of further molecular refinement (169,172,209). Alterations in this subgroup include amplification of wild-type PDGFRA, activating mutations, or intragenic rearrangements of this kinase that are age-specific, resulting in constitutively increased tyrosine kinase signaling and activation of downstream mitogen-activated protein kinase (MAPK) and PI3K pathways (210,211). Inhibiting PDGFRA with imatinib, a small molecule that also targets BCR-ABL and c-KIT, showed only very limited effects in cohorts of adults with progressive or recurrent high-grade malignant gliomas in past studies (212)(213)(214).…”

Approaches Toward Improving the Prognosis of Pediatric Patients With Glioma: Pursuing Mutant Drug Targets With Emerging Small Molecules

“…For example, it is known that PDGFR-α activates the RAS-RAF-MEK-ERK pathway, whereby it is amplified in 30% of paediatric glioma, and of those 14% have mutations. 29 Similarly, FGFR1 is a potential new target which has mutations in subsets of paediatric astrocytoma and glioblastoma multiforme. 30 Drug targeting of FGFR fusions has shown promising results and should soon be translating into clinical trials, and further understanding of the diverse mechanisms of FGFR ought to shed light on the impact of FGFR-derived therapy in the future.…”

A new era for children with diffuse intrinsic pontine glioma: hope for cure?

“…Biopsy has the advantage of providing nonpretreated material with the presence of original molecular characteristics, while tissue obtained by autopsy has the risk of treatment-related genetic changes. On the other hand, postmortem tissue collection has the benefit of providing much larger amounts of tissue, enabling analysis on the heterogeneity of the tumor [10], and also provides genetic information on the treatment-resistant subclones present at end-stage disease. Moreover, it enables the collection of normal brain tissue of the patient.…”

“…Importantly, studies show a clearly distinct genetic profile of pediatric highgrade glioma (HGG) including DIPG as compared with adult HGG [11]. Moreover, DIPG differs from pediatric HGG occurring elsewhere in the brain, since several chromosomal abnormalities appear more frequently in DIPG than in pediatric HGG, including gains of chromosomes 1q, 2p, 7p, 8q and 9q and losses in chromosomes 10q, 16q and 17p [10,[12][13][14][15] Editorial arising in the thalamus, suggesting a shared origin of a common precursor cell population [13].…”

“…Other amplified genes in DIPG are hepatocyte growth factor receptor (MET ), IGF receptor 1 (IGF1R), EGF receptors (EGFR, ERBB4 and EGFRv3), poly-ADP-ribose polymerase (PARP ), VEGFA and the associated downstream pathways including PI3K-Akt-phosphomammalian target of rapamycin (MTOR) and retinoblastoma-associated protein (RB) pathway [10,[12][13][14][15] . Puget et al performed comparative genomic hybridization and gene expression profiling on 23 biopsy samples and identified two subgroups; the first characterized by oligodendroglial features appearing largely driven by PDGFR and the second by mesenchymal and angiogenesis characteristics showing overexpression of numerous proangiogenic genes including VEGFA [13].…”