Characterizing and targeting PDGFRA alterations in pediatric high-grade glioma.
Date
2016-10-04Author
Koschmann, C
Zamler, D
MacKay, A
Robinson, D
Wu, Y-M
Doherty, R
Marini, B
Tran, D
Garton, H
Muraszko, K
Robertson, P
Leonard, M
Zhao, L
Bixby, D
Peterson, L
Camelo-Piragua, S
Jones, C
Mody, R
Lowenstein, PR
Castro, MG
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Tumor Cells, Cultured
Humans
Glioma
Brain Neoplasms
Receptor, Platelet-Derived Growth Factor alpha
Antineoplastic Agents
Survival Rate
Follow-Up Studies
Age Factors
Apoptosis
Cell Proliferation
Gene Amplification
Mutation
Adolescent
Adult
Child
Child, Preschool
Infant
Female
Male
Young Adult
Neoplasm Grading
Biomarkers, Tumor
Research team
Glioma Team
Language
eng
Date accepted
2016-08-13
License start date
2016-10
Citation
Oncotarget, 2016, 7 (40), pp. 65696 - 65706
Publisher
IMPACT JOURNALS LLC