K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas
Open accessAbstract
Pediatric glioblastomas (GBM) including diffuse intrinsic pontine gliomas (DIPG) are devastating brain tumors with no effective therapy. Here, we investigated clinical and biological impacts of histone H3.3 mutations. Forty-two DIPGs were tested for H3.3 mutations. Wild-type versus mutated (K27M-H3.3) subgroups were compared for HIST1H3B, IDH, ATRX and TP53 mutations, copy number alterations and clinical outcome. K27M-H3.3 occurred in 71 %, TP53 mutations in 77 % and ATRX mutations in 9 % of DIPGs. ATRX mutations were more frequent in older children (p < 0.0001). No G34V/R-H3.3, IDH1/2 or H3.1 mutations were identified. K27M-H3.3 DIPGs showed specific copy number changes, including all gains/amplifications of PDGFRA and MYC/PVT1 loci. Notably, all long-term survivors were H3.3 wild type and this group of patients had better overall survival. K27M-H3.3 mutation defines clinically and biologically distinct subgroups and is prevalent in DIPG, which will impact future therapeutic trial design. K27M- and G34V-H3.3 have location-based incidence (brainstem/cortex) and potentially play distinct roles in pediatric GBM pathogenesis. K27M-H3.3 is universally associated with short survival in DIPG, while patients wild-type for H3.3 show improved survival. Based on prognostic and therapeutic implications, our findings argue for H3.3-mutation testing at diagnosis, which should be rapidly integrated into the clinical decision-making algorithm, particularly in atypical DIPG.
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More than 90% of pediatric high-grade gliomas arising in the brain midline, including diffuse intrinsic pontine gliomas, carry K27M mutations in an H3 variant.
“Indeed, more than 90% of pHGG in the brain midline, including the particularly deadly diffuse intrinsic pontine gliomas (DIPG), carry lysine 27 to methionine (K27M) mutations in an H3 variant (H3F3A/H3.3, HIST1H3B or HIST1H3C/H3.1 and rarely HIST2H3B/H3.2)”
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 Khuong-Quang et al., 2012
Loss-of-function mutations in ATRX occur with increasing frequency in older patients.
“loss-of-function mutations in ATRX, which occur with increasing frequency in older patients”
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 Khuong-Quang et al., 2012
PDGFRA amplifications and rare mutations often co-occur with H3.3K27M and TP53 mutations.
“Moreover, amplifications and rare mutations of the platelet-derived growth factor receptor alpha gene (PDGFRA) often co-occur with H3.3K27M and TP53 mutations, indicating a potential role of this receptor in tumorigenesis”
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 Khuong-Quang et al., 2012
G34R/V mutations in H3.3 occur in 36% of pediatric high-grade gliomas in the cerebral hemispheres.
“while mutations of glycine 34 to arginine or valine (G34R/V) in H3.3 occur in 36% of pHGG in the cerebral hemispheres”
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 Khuong-Quang et al., 2012
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- Authors
- Khuong-Quang, D.-A., Buczkowicz, P., Rakopoulos, P., Liu, X.-Y., Fontebasso, A. M., Bouffet, E., Bartels, U., Albrecht, S., Schwartzentruber, J., Letourneau, L., Bourgey, M., Bourque, G., Montpetit, A., Bourret, G., Lepage, P., Fleming, A., Lichter, P., Kool, M., von Deimling, A., Sturm, D., Korshunov, A., Faury, D., Jones, D. T., Majewski, J., Pfister, S. M., Jabado, N., & Hawkins, C.
- Affiliations
- McGill University (CA)
- University of Toronto (CA)
- Hospital for Sick Children (CA)
- Montreal Children's Hospital (CA)
- McGill University and Génome Québec Innovation Centre (CA)
- German Cancer Research Center (DE)
- Corresponding author
- Jabado, Nada
- Hawkins, Cynthia
- ORCID
- Venue
- Acta Neuropathologica
- Published
- 2012-06-03
- Volume
- 124
- Issue
- 3
- Pages
- 439-447
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC3422615
- OpenAlex
- W2028643362
- Cited by
- 1,028
- References
- 27
- Citations by year
- 2026: 48 · 2025: 55 · 2024: 70 · 2023: 96 · 2022: 80 · 2021: 100 · 2020: 100 · 2019: 86 · 2018: 68 · 2017: 91 · 2016: 50 · 2015: 57 · 2014: 66 · 2013: 50 · 2012: 11
- FWCI
- 28.10
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Acta Neuropathologica (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- Funders
- Genome Canada
- Genome British Columbia
- Bundesministerium für Bildung und Forschung
- Deutsche Krebshilfe (108456)
- Fondation des Etoiles
- Canadian Institutes of Health Research (MOP115004)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- diffuse intrinsic pontine glioma, pediatric glioblastoma, TP53 mutation, ATRX mutation, IDH mutation, copy number alterations, PDGFRA amplification, overall survival, prognostic subgroups
- MeSH terms
- Adolescent, Child, Child, Preschool, Female, Glioma, Histones, Humans, Infant, Male, Mutation, Pons, Prognosis, Survival Rate, Brain Stem Neoplasms, Gene Expression Profiling
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