title: Characterizing and targeting PDGFRA alterations in pediatric high-grade glioma.
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.
authors: Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.|Department of Neurosurgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors: Carl
authors: C
authors: Koschmann
authors: Department of Neurosurgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors: Daniel
authors: D
authors: Zamler
authors: Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, London, SM2 5NG, UK.
authors: Alan
authors: A
authors: MacKay
authors: Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors: Dan
authors: D
authors: Robinson
authors: Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors: Yi-Mi
authors: YM
authors: Wu
authors: Department of Neurosurgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors: Robert
authors: R
authors: Doherty
authors: Department of Pharmacology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors: Bernard
authors: B
authors: Marini
authors: Department of Neurosurgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors: Dustin
authors: D
authors: Tran
authors: Department of Neurosurgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors: Hugh
authors: H
authors: Garton
authors: Department of Neurosurgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors: Karin
authors: K
authors: Muraszko
authors: Department of Pediatrics, Division of Neurology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors: Patricia
authors: P
authors: Robertson
authors: Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors: Marcia
authors: M
authors: Leonard
authors: Department of Biostatistics, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors: Lili
authors: L
authors: Zhao
authors: Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors: Dale
authors: D
authors: Bixby
authors: Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors: Luke
authors: L
authors: Peterson
authors: Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors: Sandra
authors: S
authors: Camelo-Piragua
authors: Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, London, SM2 5NG, UK.
authors: Chris
authors: C
authors: Jones
authors: Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors: Rajen
authors: R
authors: Mody
authors: Department of Neurosurgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.|Department of Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors: Pedro R
authors: PR
authors: Lowenstein
authors: Department of Neurosurgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.|Department of Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors: Maria G
authors: MG
authors: Castro
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D005784:Gene Amplification; D005910:Glioma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D060787:Neoplasm Grading; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D020796:Receptor, Platelet-Derived Growth Factor alpha
keywords: PDGFRA amplification; PDGFRA mutation; brain tumor; pediatric high-grade glioma; tyrosine kinase inhibitor