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Characterizing and targeting PDGFRA alterations in pediatric high-grade glioma

2016; Impact Journals LLC; Volume: 7; Issue: 40 Linguagem: Inglês

10.18632/oncotarget.11602

1949-2553

Carl Koschmann, Daniel Zamler, Alan Mackay, Dan R. Robinson, Yi-Mi Wu, Robert Doherty, Bernard L. Marini, Dustin Tran, Hugh Garton, Karin M. Muraszko, Patricia L. Robertson, Marcia Leonard, Lili Zhao, Dale L. Bixby, Luke F. Peterson, Sandra Camelo‐Piragua, Chris Jones, Rajen Mody, Pedro R. Löwenstein, María G. Castro,

Cancer, Hypoxia, and Metabolism

// Carl Koschmann 1, 2 , Daniel Zamler 2 , Alan MacKay 3 , Dan Robinson 4 , Yi-Mi Wu 4 , Robert Doherty 2 , Bernard Marini 5 , Dustin Tran 2 , Hugh Garton 2 , Karin Muraszko 2 , Patricia Robertson 6 , Marcia Leonard 1 , Lili Zhao 7 , Dale Bixby 8 , Luke Peterson 8 , Sandra Camelo-Piragua 4 , Chris Jones 3 , Rajen Mody 1 , Pedro R. Lowenstein 2, 9 , Maria G. Castro 2, 9 1 Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA 2 Department of Neurosurgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA 3 Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, London, SM2 5NG, UK 4 Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA 5 Department of Pharmacology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA 6 Department of Pediatrics, Division of Neurology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA 7 Department of Biostatistics, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA 8 Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA 9 Department of Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA Correspondence to: Maria G. Castro, email: mariacas@med.umich.edu Keywords: pediatric high-grade glioma, PDGFRA amplification, PDGFRA mutation, brain tumor, tyrosine kinase inhibitor Received: May 06, 2016     Accepted: August 13, 2016     Published: August 25, 2016 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.