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

Autor: Auffret L; Molecular Predictors and New Targets in Oncology, Inserm, Gustave Roussy, Université Paris-Saclay, Villejuif, France., Ajlil Y; Molecular Predictors and New Targets in Oncology, Inserm, Gustave Roussy, Université Paris-Saclay, Villejuif, France., Tauziède-Espariat A; Department of Neuropathology, GHU Paris-Psychiatrie et Neurosciences, Sainte-Anne Hospital, Paris, France.; UMR 1266, IMA-Brain, Institut de Psychiatrie et Neurosciences de Paris, Inserm, Paris, France., Kergrohen T; Molecular Predictors and New Targets in Oncology, Inserm, Gustave Roussy, Université Paris-Saclay, Villejuif, France.; Département de Cancérologie de L'Enfant et de L'Adolescent, Gustave Roussy, Université Paris-Saclay, Villejuif, France., Puiseux C; Department of Pediatric Oncology, Rennes University Hospital, Rennes, France., Riffaud L; Department of Pediatric Neurosurgery, Rennes University Hospital, Rennes, France., Blouin P; Department of Pediatric Hematology, CHRU de Tours, Tours, France., Bertozzi AI; Department of Pediatric Hematology-Oncology, Hôpital des Enfants, Toulouse, France., Leblond P; Institute of Pediatric Hematology and Oncology, Centre Léon Bérard, Lyon, France., Blomgren K; Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.; Pediatric Hematology and Oncology, Karolinska University Hospital, Stockholm, Sweden., Froelich S; Service de Neurochirurgie-Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris, France., Picca A; 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., Touat M; 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., Sanson M; 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., Beccaria K; Molecular Predictors and New Targets in Oncology, Inserm, Gustave Roussy, Université Paris-Saclay, Villejuif, France.; Department of Pediatric Neurosurgery, Hôpital Necker-Enfants Malades, AP-HP, Université Paris Cité, Paris, France., Blauwblomme T; Department of Pediatric Neurosurgery, Hôpital Necker-Enfants Malades, AP-HP, Université Paris Cité, Paris, France., Dangouloff-Ros V; Department of Pediatric Radiology, Hôpital Necker-Enfants Malades, AP-HP, Université Paris-Cité, Paris, France.; INSERM U1163, Institut Imagine, Université Paris Cité, Paris, France., Boddaert N; Department of Pediatric Radiology, Hôpital Necker-Enfants Malades, AP-HP, Université Paris-Cité, Paris, France.; INSERM U1163, Institut Imagine, Université Paris Cité, Paris, France., Varlet P; Department of Neuropathology, GHU Paris-Psychiatrie et Neurosciences, Sainte-Anne Hospital, Paris, France.; UMR 1266, IMA-Brain, Institut de Psychiatrie et Neurosciences de Paris, Inserm, Paris, France., Debily MA; Molecular Predictors and New Targets in Oncology, Inserm, Gustave Roussy, Université Paris-Saclay, Villejuif, France.; Département de Biologie, Université Évry Paris-Saclay, Évry, France., Grill J; Molecular Predictors and New Targets in Oncology, Inserm, Gustave Roussy, Université Paris-Saclay, Villejuif, France. jacques.grill@gustaveroussy.fr.; Département de Cancérologie de L'Enfant et de L'Adolescent, Gustave Roussy, Université Paris-Saclay, Villejuif, France. jacques.grill@gustaveroussy.fr., Castel D; Molecular Predictors and New Targets in Oncology, Inserm, Gustave Roussy, Université Paris-Saclay, Villejuif, France. david.castel@gustaveroussy.fr.; Département de Cancérologie de L'Enfant et de L'Adolescent, Gustave Roussy, Université Paris-Saclay, Villejuif, France. david.castel@gustaveroussy.fr.
Jazyk: angličtina
Zdroj: Acta neuropathologica [Acta Neuropathol] 2023 Dec 08; Vol. 147 (1), pp. 2. Date of Electronic Publication: 2023 Dec 08.
DOI: 10.1007/s00401-023-02651-4
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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