Abstract
Pediatric high-grade glioma (HGG, WHO Grade III and IV) is a devastating brain tumor with a median survival of less than two years. PDGFRA is frequently mutated/amplified in pediatric HGG, but the significance of this finding has not been fully characterized. We hypothesize that alterations of PDGFRA will promote distinct prognostic and treatment implications in pediatric HGG. In order to characterize the impact of PDGFR pathway alterations, we integrated genomic data from pediatric HGG patients (n=290) from multiple pediatric datasets and sequencing platforms. Integration of multiple human datasets showed that PDGFRA mutation, but not amplification, was associated with older age in pediatric HGG (P= <0.0001). In multivariate analysis, PDGFRA mutation was correlated with worse prognosis (P = 0.026), while PDGFRA amplification was not (P = 0.11). By Kaplan-Meier analysis, non-brainstem HGG with PDGFRA amplification carried a worse prognosis than non-brainstem HGG without PDGFRA amplification (P = 0.021). There were no pediatric patients with PDGFRA-amplified HGG that survived longer than two years. Additionally, we performed paired molecular profiling (germline / tumor / primary cell culture) and targeting of an infant thalamic HGG with amplification and outlier increased expression of PDGFRA. Dasatinib inhibited proliferation most effectively. In summary, integration of the largest genomic dataset of pediatric HGG to date, allowed us to highlight that PDGFRA mutation is found in older pediatric patients and that PDGFRA amplification is prognostic in non-brainstem HGG. Future precision-medicine based clinical trials for pediatric patients with PDGFRA-altered HGG should consider the optimized delivery of dasatinib.
Highlights
Pediatric high-grade glioma (WHO Grade III and IV) is a devastating brain tumor carrying a poor prognosis
Integration of the largest genomic dataset of pediatric highgrade glioma (HGG) to date, allowed us to highlight that PDGFRA mutation is found in older pediatric patients and that PDGFRA amplification is prognostic in non-brainstem HGG
We integrated multiple sequencing platforms used for these datasets to produce full somatic sequence and copy number information on 290 pediatric high-grade glioma (HGG) samples, including 137 diffuse intrinsic pontine glioma (DIPG) and 153 nonbrainstem HGG (22 anaplastic astrocytomas (WHO grade III), 125 glioblastomas (WHO grade IV), 1 anaplastic ganglioglioma, 1 gliomatosis cerebri, and 4 high-grade glioma, not otherwise specified)
Summary
Pediatric high-grade glioma (WHO Grade III and IV) is a devastating brain tumor carrying a poor prognosis. Despite histologic similarities to adult highgrade glioma (HGG), there are important differences from tumors arising in younger patients. Pediatric HGG arises in different locations, more often in midline structures such as the brainstem and thalamus. Pediatric high grade gliomas almost always develop de novo as high-grade lesions, as opposed to secondary GBM seen in some adult patients [1,2,3]. Infants are often treated with intensive multi-agent chemo with the goal of avoiding or delaying radiation [4]. These treatments are rarely curative, and 70-90% of patients with pediatric HGG will die within two years of diagnosis [2]
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