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Novel Oncogenic PDGFRA Mutations in Pediatric High-Grade Gliomas
Open accessPublished version of a preprint
Abstract
The outcome for children with high-grade gliomas (HGG) remains dismal, with a 2-year survival rate of only 10% to 30%. Diffuse intrinsic pontine glioma (DIPG) comprise a subset of HGG that arise in the brainstem almost exclusively in children. Genome-wide analyses of copy number imbalances previously showed that platelet-derived growth factor receptor α (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 of 90) of nonbrainstem pediatric HGGs and 4.7% (2 of 43) of DIPGs, including missense mutations and in-frame deletions and insertions not previously described. Forty percent of tumors with mutation showed concurrent amplification, whereas 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 nonbrainstem pediatric HGG and 57 DIPGs. Thus, a distinct spectrum of mutations confers constitutive receptor activation and oncogenic activity to PDGFRα in childhood HGG.
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“suggesting that, unlike WT PDGFRA, PDGFRAD842V does not require H3.3K27M to drive tumorigenesis in vivo”
From H3.3K27M Cooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas (2017) · cites this paper as Paugh et al., 2013
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Metadata
- Authors
- Paugh, B. S., Zhu, X., Qu, C., Endersby, R., Diaz, A. K., Zhang, J., Bax, D. A., Carvalho, D., Reis, R. M., Onar-Thomas, A., Broniscer, A., Wetmore, C., Zhang, J., Jones, C., Ellison, D. W., & Baker, S. J.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Authors' Affiliations: Departments of 1Developmental Neurobiology, 2Computational Biology, 3Biostatistics, 4Oncology, and 5Pathology, St. Jude Children's Research Hospital; 6Interdisciplinary Biomedical Science Program, University of Tennessee Health Sciences Center, Memphis, Tennessee; 7Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Perth, Australia; 8Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom; and 9Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
- Corresponding author
- Baker, Suzanne J.
- ORCID
- Venue
- Cancer Research
- Published
- 2013-10-14
- Volume
- 73
- Issue
- 20
- Pages
- 6219-6229
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3800209
- OpenAlex
- W2124839835
- Cited by
- 235
- References
- 58
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 17 · 2023: 14 · 2022: 23 · 2021: 25 · 2020: 14 · 2019: 14 · 2018: 22 · 2017: 26 · 2016: 17 · 2015: 14 · 2014: 23 · 2013: 3
- FWCI
- 9.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Funders
- V Foundation for Cancer Research
- Cure Starts Now Foundation
- American Lebanese Syrian Associated Charities
- Arog Pharmaceuticals
- Brain Tumour Charity
- National Institutes of Health
- National Cancer Institute (R01CA135554, P01CA096832, P30CA021765)
- Topics
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal Tumor Research and Treatment
- Keywords
- PDGFRA mutation, pediatric high-grade glioma, diffuse intrinsic pontine glioma, somatic activating mutations, ligand-independent receptor activation, PDGFR inhibitors, oncogenic receptor tyrosine kinase, exon deletion, brainstem glioma
- MeSH terms
- Adolescent, Animals, Brain Neoplasms, Child, Child, Preschool, Glioma, Humans, Mutation, Receptor, Platelet-Derived Growth Factor alpha, Gene Expression Profiling, Mice, Genome-Wide Association Study
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