Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma
Open accessAbstract
Pediatric midline high-grade astrocytomas (mHGAs) are incurable with few treatment targets identified. Most tumors harbor mutations encoding p.Lys27Met in histone H3 variants. In 40 treatment-naive mHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with histone H3.1 p.Lys27Met substitution, whereas FGFR1 mutations or fusions occur in thalamic tumors associated with histone H3.3 p.Lys27Met substitution. Hyperactivation of the bone morphogenetic protein (BMP)-ACVR1 developmental pathway in mHGAs harboring ACVR1 mutations led to increased levels of phosphorylated SMAD1, SMAD5 and SMAD8 and upregulation of BMP downstream early-response genes in tumor cells. Global DNA methylation profiles were significantly associated with the p.Lys27Met alteration, regardless of the mutant histone H3 variant and irrespective of tumor location, supporting the role of this substitution in driving the epigenetic phenotype. This work considerably expands the number of potential treatment targets and further justifies pretreatment biopsy in pediatric mHGA as a means to orient therapeutic efforts in this disease.
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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 Fontebasso et al., 2014
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 Fontebasso et al., 2014
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 Fontebasso et al., 2014
Alterations affecting the p53 pathway occur in about 87% of H3.3K27M tumors.
“These include alterations affecting the p53 pathway in ~87% of H3.3K27M tumors”
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 Fontebasso et al., 2014
A large proportion of thalamic H3.3K27M tumors and the majority of cortical H3.3G34R/V tumors are more focal at initial presentation and display loss of ATRX.
“We have reported elsewhere that a large proportion of thalamic H3.3K27M tumors, and the majority of cortical H3.3G34R/V tumors, are more focal at initial presentation and display loss of ATRX (Fontebasso et al., 2014).”
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 Fontebasso et al., 2014
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- Authors
- Fontebasso, A. M., Papillon-Cavanagh, S., Schwartzentruber, J., Nikbakht, H., Gerges, N., Fiset, P.-O., Bechet, D., Faury, D., De Jay, N., Ramkissoon, L. A., Corcoran, A., Jones, D. T. W., Sturm, D., Johann, P., Tomita, T., Goldman, S., Nagib, M., Bendel, A., Goumnerova, L., Bowers, D. C., Leonard, J. R., Rubin, J. B., Alden, T., Browd, S., Geyer, J. R., Leary, S., Jallo, G., Cohen, K., Gupta, N., Prados, M. D., Carret, A.-S., Ellezam, B., Crevier, L., Klekner, A., Bognar, L., Hauser, P., Garami, M., Myseros, J., Dong, Z., Siegel, P. M., Malkin, H., Ligon, A. H., Albrecht, S., Pfister, S. M., Ligon, K. L., Majewski, J., Jabado, N., & Kieran, M. W.
- Affiliations
- Montreal Children's Hospital (CA)
- Wellcome Sanger Institute (GB)
- McGill University (CA)
- Dana-Farber Cancer Institute (US)
- German Cancer Research Center (DE)
- Northwestern University (US)
- Boston Children's Hospital (US)
- Children's Minnesota (US)
- The University of Texas Southwestern Medical Center (US)
- Washington University in St. Louis (US)
- Seattle Children's Hospital (US)
- Johns Hopkins University (US)
- University of California, San Francisco (US)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Children's National (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Ligon, Keith L
- Majewski, Jacek
- Jabado, Nada
- Kieran, Mark W
- ORCID
- Schwartzentruber, Jeremy
- Nikbakht, Hamid
- Fiset, Pierre-Olivier
- Faury, Damien
- Ramkissoon, Lori A
- Jones, David T W
- Sturm, Dominik
- Johann, Pascal
- Tomita, Tadanori
- Goldman, Stewart
- Bendel, Anne
- Goumnerova, Liliana
- Bowers, Daniel C
- Rubin, Joshua B
- Alden, Tord
- Browd, Samuel
- Leary, Sarah
- Jallo, George
- Cohen, Kenneth
- Gupta, Nalin
- Prados, Michael D
- Carret, Anne-Sophie
- Ellezam, Benjamin
- Siegel, Peter M
- Ligon, Azra H
- Albrecht, Steffen
- Pfister, Stefan M
- Ligon, Keith L
- Majewski, Jacek
- Jabado, Nada
- Kieran, Mark W
- Venue
- Nature Genetics
- Published
- 2014-04-06
- Volume
- 46
- Issue
- 5
- Pages
- 462-466
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC4282994
- OpenAlex
- W1980767402
- Cited by
- 465
- References
- 37
- Citations by year
- 2026: 15 · 2025: 12 · 2024: 40 · 2023: 44 · 2022: 32 · 2021: 38 · 2020: 45 · 2019: 36 · 2018: 42 · 2017: 57 · 2016: 39 · 2015: 36 · 2014: 29
- FWCI
- 27.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Repository of the Academy's Library (Library of the Hungarian Academy of Sciences) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion, other-oa)
- Semmelweis University Repository (Semmelweis University) (submittedVersion)
- Funders
- Dana-Farber Cancer Institute
- McGill University
- Genome Canada
- Children's Hospital Foundation
- Génome Québec
- Hungarian Scientific Research Fund
- Canadian Institutes of Health Research
- National Cancer Institute (P01CA142536, P30CA060553)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- ACVR1 mutation, somatic mutations, FGFR1 mutation, BMP signaling, Smad1/5/8 phosphorylation, DNA methylation, epigenetic regulation, thalamic tumors, tumor location, treatment goals, pre-treatment biopsy
- MeSH terms
- Animals, Astrocytoma, Base Sequence, Brain Neoplasms, Child, Humans, Immunohistochemistry, Molecular Sequence Data, Mutation, Genome, Human, Gene Expression Regulation, Neoplastic, In Situ Hybridization, Fluorescence, Sequence Analysis, DNA, DNA Methylation, Bone Morphogenetic Proteins, Activin Receptors, Type I, Smad Proteins, DNA Copy Number Variations
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