A new subtype of diffuse midline glioma, H3 K27 and BRAF/FGFR1 co-altered: a clinico-radiological and histomolecular characterisation

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Abstract

Diffuse midline gliomas (DMG) H3 K27-altered are incurable grade 4 gliomas and represent a major challenge in neuro-oncology. This tumour type is now classified in four subtypes by the 2021 edition of the WHO Classification of the Central Nervous System (CNS) tumours. However, the H3.3-K27M subgroup still appears clinically and molecularly heterogeneous. Recent publications reported that rare patients presenting a co-occurrence of H3.3K27M with BRAF or FGFR1 alterations tended to have a better prognosis. To better study the role of these co-driver alterations, we assembled a large paediatric and adult cohort of 29 tumours H3K27-altered with co-occurring activating mutation in BRAF or FGFR1 as well as 31 previous cases from the literature. We performed a comprehensive histological, radiological, genomic, transcriptomic and DNA methylation analysis. Interestingly, unsupervised t-distributed Stochastic Neighbour Embedding (tSNE) analysis of DNA methylation profiles regrouped BRAF ^V600E and all but one FGFR1 ^MUT DMG in a unique methylation cluster, distinct from the other DMG subgroups and also from ganglioglioma (GG) or high-grade astrocytoma with piloid features (HGAP). This new DMG subtype harbours atypical radiological and histopathological profiles with calcification and/or a solid tumour component both for BRAF ^V600E and FGFR1 ^MUT cases. The analyses of a H3.3-K27M BRAF ^V600E tumour at diagnosis and corresponding in vitro cellular model showed that mutation in H3-3A was the first event in the oncogenesis. Contrary to other DMG, these tumours occur more frequently in the thalamus (70% for BRAF ^V600E and 58% for FGFR1 ^MUT) and patients have a longer overall survival with a median above three years. In conclusion, DMG, H3 K27 and BRAF/FGFR1 co-altered represent a new subtype of DMG with distinct genotype/phenotype characteristics, which deserve further attention with respect to trial interpretation and patient management.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00401-023-02651-4.

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Most cited references 44

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The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary.

David N Louis, Arie Perry, Guido Reifenberger … (2016)

The 2016 World Health Organization Classification of Tumors of the Central Nervous System is both a conceptual and practical advance over its 2007 predecessor. For the first time, the WHO classification of CNS tumors uses molecular parameters in addition to histology to define many tumor entities, thus formulating a concept for how CNS tumor diagnoses should be structured in the molecular era. As such, the 2016 CNS WHO presents major restructuring of the diffuse gliomas, medulloblastomas and other embryonal tumors, and incorporates new entities that are defined by both histology and molecular features, including glioblastoma, IDH-wildtype and glioblastoma, IDH-mutant; diffuse midline glioma, H3 K27M-mutant; RELA fusion-positive ependymoma; medulloblastoma, WNT-activated and medulloblastoma, SHH-activated; and embryonal tumour with multilayered rosettes, C19MC-altered. The 2016 edition has added newly recognized neoplasms, and has deleted some entities, variants and patterns that no longer have diagnostic and/or biological relevance. Other notable changes include the addition of brain invasion as a criterion for atypical meningioma and the introduction of a soft tissue-type grading system for the now combined entity of solitary fibrous tumor / hemangiopericytoma-a departure from the manner by which other CNS tumors are graded. Overall, it is hoped that the 2016 CNS WHO will facilitate clinical, experimental and epidemiological studies that will lead to improvements in the lives of patients with brain tumors.

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The 2021 WHO Classification of Tumors of the Central Nervous System: a summary

David N Louis, Arie Perry, Pieter Wesseling … (2021)

The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, is the sixth version of the international standard for the classification of brain and spinal cord tumors. Building on the 2016 updated fourth edition and the work of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy, the 2021 fifth edition introduces major changes that advance the role of molecular diagnostics in CNS tumor classification. At the same time, it remains wedded to other established approaches to tumor diagnosis such as histology and immunohistochemistry. In doing so, the fifth edition establishes some different approaches to both CNS tumor nomenclature and grading and it emphasizes the importance of integrated diagnoses and layered reports. New tumor types and subtypes are introduced, some based on novel diagnostic technologies such as DNA methylome profiling. The present review summarizes the major general changes in the 2021 fifth edition classification and the specific changes in each taxonomic category. It is hoped that this summary provides an overview to facilitate more in-depth exploration of the entire fifth edition of the WHO Classification of Tumors of the Central Nervous System.

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DNA methylation-based classification of central nervous system tumours

David Capper, David Jones, Martin Sill … (2018)

Summary Accurate pathological diagnosis is crucial for optimal management of cancer patients. For the ~100 known central nervous system (CNS) tumour entities, standardization of the diagnostic process has been shown to be particularly challenging - with substantial inter-observer variability in the histopathological diagnosis of many tumour types. We herein present the development of a comprehensive approach for DNA methylation-based CNS tumour classification across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that availability of this method may have substantial impact on diagnostic precision compared with standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility we have designed a free online classifier tool (www.molecularneuropathology.org) requiring no additional onsite data processing. Our results provide a blueprint for the generation of machine learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.

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Author and article information

Contributors

Jacques Grill: jacques.grill@gustaveroussy.fr

David Castel: david.castel@gustaveroussy.fr

Journal

Journal ID (nlm-ta): Acta Neuropathol

Journal ID (iso-abbrev): Acta Neuropathol

Title: Acta Neuropathologica

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0001-6322

ISSN (Electronic): 1432-0533

Publication date (Electronic): 8 December 2023

Publication date PMC-release: 8 December 2023

Publication date (Print): 2024

Volume: 147

Issue: 1

Electronic Location Identifier: 2

Affiliations

[1 ]GRID grid.460789.4, ISNI 0000 0004 4910 6535, Molecular Predictors and New Targets in Oncology, Inserm, Gustave Roussy, , Université Paris-Saclay, ; Villejuif, France

[2 ]Department of Neuropathology, GHU Paris-Psychiatrie et Neurosciences, Sainte-Anne Hospital, ( https://ror.org/040pk9f39) Paris, France

[3 ]GRID grid.7429.8, ISNI 0000000121866389, UMR 1266, IMA-Brain, Institut de Psychiatrie et Neurosciences de Paris, , Inserm, ; Paris, France

[4 ]Département de Cancérologie de L’Enfant et de L’Adolescent, Gustave Roussy, Université Paris-Saclay, ( https://ror.org/03xjwb503) Villejuif, France

[5 ]Department of Pediatric Oncology, Rennes University Hospital, ( https://ror.org/05qec5a53) Rennes, France

[6 ]Department of Pediatric Neurosurgery, Rennes University Hospital, ( https://ror.org/05qec5a53) Rennes, France

[7 ]GRID grid.411167.4, ISNI 0000 0004 1765 1600, Department of Pediatric Hematology, , CHRU de Tours, ; Tours, France

[8 ]Department of Pediatric Hematology-Oncology, Hôpital des Enfants, ( https://ror.org/044hb6b32) Toulouse, France

[9 ]Institute of Pediatric Hematology and Oncology, Centre Léon Bérard, ( https://ror.org/01cmnjq37) Lyon, France

[10 ]Department of Women’s and Children’s Health, Karolinska Institutet, ( https://ror.org/056d84691) Stockholm, Sweden

[11 ]Pediatric Hematology and Oncology, Karolinska University Hospital, ( https://ror.org/00m8d6786) Stockholm, Sweden

[12 ]GRID grid.50550.35, ISNI 0000 0001 2175 4109, Service de Neurochirurgie-Hôpital Lariboisière, , Assistance Publique-Hôpitaux de Paris, Université Paris Cité, ; Paris, France

[13 ]GRID grid.50550.35, ISNI 0000 0001 2175 4109, Inserm U1127, CNRS UMR 7225, Institut du Cerveau, ICM, Charles Foix, Service de Neurologie 2-Mazarin, , Sorbonne Université, AP-HP, Hôpitaux Universitaires la Pitié Salpêtrière, ; Paris, France

[14 ]GRID grid.508487.6, ISNI 0000 0004 7885 7602, Department of Pediatric Neurosurgery, , Hôpital Necker-Enfants Malades, AP-HP, Université Paris Cité, ; Paris, France

[15 ]GRID grid.508487.6, ISNI 0000 0004 7885 7602, Department of Pediatric Radiology, , Hôpital Necker-Enfants Malades, AP-HP, Université Paris-Cité, ; Paris, France

[16 ]GRID grid.508487.6, ISNI 0000 0004 7885 7602, INSERM U1163, Institut Imagine, , Université Paris Cité, ; Paris, France

[17 ]Département de Biologie, Université Évry Paris-Saclay, ( https://ror.org/03xjwb503) Évry, France

Article

Publisher ID: 2651

DOI: 10.1007/s00401-023-02651-4

PMC ID: 10709479

PubMed ID: 38066305

SO-VID: acfde94f-eafa-41a0-bf7a-157cc7eec708

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 3 August 2023

Date revision received : 22 October 2023

Date accepted : 24 October 2023

Funding

Funded by: Charity Etoile de Martin

Funded by: Charity Imagine for Margo

Custom metadata

ScienceOpen disciplines: Neurology

Keywords: paediatric-type high-grade glioma,adult glioma,midline glioma,braf-v600e mutation,fgfr1 mutation,dna methylation profiling

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ScienceOpen disciplines: Neurology

Keywords: paediatric-type high-grade glioma, adult glioma, midline glioma, braf-v600e mutation, fgfr1 mutation, dna methylation profiling

A new subtype of diffuse midline glioma, H3 K27 and BRAF/FGFR1 co-altered: a clinico-radiological and histomolecular characterisation

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Abstract

Supplementary Information

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Karger: Neurology and Neuroscience

Most cited references 44

The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary.

The 2021 WHO Classification of Tumors of the Central Nervous System: a summary

DNA methylation-based classification of central nervous system tumours

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