title: Co-occurrence of histone H3 K27M and BRAF V600E mutations in paediatric midline grade I ganglioglioma.
abstract: Ganglioglioma (GG) is a grade I tumor characterized by alterations in the MAPK pathway, including BRAF V600E mutation. Recently, diffuse midline glioma with an H3 K27M mutation was added to the WHO 2016 classification as a new grade IV entity. As co-occurrence of H3 K27M and BRAF V600E mutations has been reported in midline tumors and anaplastic GG, we searched for BRAF V600E and H3 K27M mutations in a series of 54 paediatric midline grade I GG (midline GG) to determine the frequency of double mutations and its relevance for prognosis. Twenty-seven patients (50%) possessed the BRAF V600E mutation. The frequency of the co-occurrence of H3F3A/BRAF mutations at diagnosis was 9.3%. No H3 K27M mutation was detected in the absence of the BRAF V600E mutation. Double-immunostaining revealed that BRAF V600E and H3 K27M mutant proteins were present in both the glial and neuronal components. Immunopositivity for the BRAF V600E mutant protein correlated with BRAF mutation status as detected by massARRAY or digital droplet PCR. The median follow-up of patients with double mutation was 4 years. One patient died of progressive disease 8 years after diagnosis, whereas the four other patients were all alive with stable disease at the last clinical follow-up (at 9 months, 1 year and 7 years) without adjuvant therapy. We demonstrate in this first series of midline GGs that the H3 K27M mutation can occur in association with the BRAF V600E mutation in grade I glioneuronal tumors. Despite the presence of H3 K27M mutations, these cases should not be graded and treated as grade IV tumors because they have a better spontaneous outcome than classic diffuse midline H3 K27M-mutant glioma. These data suggest that H3 K27M cannot be considered a specific hallmark of grade IV diffuse gliomas and highlight the importance of integrated histomolecular diagnosis in paediatric brain tumors.
authors.affiliation: Department of Neuropathology, Sainte-Anne Hospital, Paris, France.|Paris V Descartes University, Paris, France.|Institut National de la Santé et de la Recherche Médicale, INSERM Unit 1000 "Neuroimaging & Psychiatry,", Université Paris Sud, Orsay.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Pagès
authors.affiliation: Department of Paediatric Neurosurgery, Necker Enfants Malades Hospital, Paris, France.
authors.forename: Kevin
authors.initials: K
authors.lastname: Beccaria
authors.affiliation: Department of Paediatric Neuroradiology, Necker Enfants Malades Hospital, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.affiliation: Department of Biochemistry, Paul Brousse Hospital, Paris, France.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Saffroy
authors.affiliation: Department of Neuropathology, Sainte-Anne Hospital, Paris, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Besnard
authors.affiliation: UMR8203 "Vectorologie et Thérapeutiques Anticancéreuses," CNRS, Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, Villejuif, 94805, France.|Département de Cancérologie de l'Enfant et de l'Adolescent, Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, Villejuif, 94805, France.
authors.forename: David
authors.initials: D
authors.lastname: Castel
authors.affiliation: Service de transfert d'Oncologie Biologique, LBM APHM Marseille, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Fina
authors.affiliation: APHM, Hôpital de la Timone, Service d'Anatomie Pathologique et de Neuropathologie, Marseille, France.
authors.forename: Doriane
authors.initials: D
authors.lastname: Barets
authors.affiliation: UMR8203 "Vectorologie et Thérapeutiques Anticancéreuses," CNRS, Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, Villejuif, 94805, France.|Département de Cancérologie de l'Enfant et de l'Adolescent, Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, Villejuif, 94805, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Barret
authors.affiliation: Departement de Biologie et Pathologie Médicales, Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, Villejuif, 94805, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Lacroix
authors.affiliation: Department of Neuropathology, Laboratoire Escourolle, Hôpitaux Universitaires Pitié Salpêtrière Charles Foix, AP-HP, Paris, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Bielle
authors.affiliation: Department of Neuropathology, Sainte-Anne Hospital, Paris, France.
authors.forename: Felipe
authors.initials: F
authors.lastname: Andreiuolo
authors.affiliation: Department of Neuropathology, Sainte-Anne Hospital, Paris, France.
authors.forename: Arnault
authors.initials: A
authors.lastname: Tauziède-Espariat
authors.affiliation: APHM, Hôpital de la Timone, Service d'Anatomie Pathologique et de Neuropathologie, Marseille, France.|Aix-Marseille Université, Inserm, CRO2 UMR_S 911, Marseille, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Figarella-Branger
authors.affiliation: Department of Paediatric Neurosurgery, Necker Enfants Malades Hospital, Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Puget
authors.affiliation: UMR8203 "Vectorologie et Thérapeutiques Anticancéreuses," CNRS, Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, Villejuif, 94805, France.|Département de Cancérologie de l'Enfant et de l'Adolescent, Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, Villejuif, 94805, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Grill
authors.affiliation: Department of Neuropathology, Sainte-Anne Hospital, Paris, France.|Paris V Descartes University, Paris, France.|Infection & Epidemiology Department, Human Histopathology and Animal Models Unit, Institut Pasteur, Paris, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Chrétien
authors.affiliation: Department of Neuropathology, Sainte-Anne Hospital, Paris, France.|Paris V Descartes University, Paris, France.|Institut National de la Santé et de la Recherche Médicale, INSERM Unit 1000 "Neuroimaging & Psychiatry,", Université Paris Sud, Orsay.
authors.forename: Pascale
authors.initials: P
authors.lastname: Varlet
mesh_terms: D000293:Adolescent; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D018303:Ganglioglioma / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D006657:Histones / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009154:Mutation; D060787:Neoplasm Grading; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D013120:Spinal Cord Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D016896:Treatment Outcome
chemical_list: D006657:Histones; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF V600E; H3 K27M; ganglioglioma; midline