title: Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes.
abstract: Diffuse intrinsic pontine glioma (DIPG) is the most severe paediatric solid tumour, with no significant therapeutic progress made in the past 50 years. Recent studies suggest that diffuse midline glioma, H3-K27M mutant, may comprise more than one biological entity. The aim of the study was to determine the clinical and biological variables that most impact their prognosis. Ninety-one patients with classically defined DIPG underwent a systematic stereotactic biopsy and were included in this observational retrospective study. Histone H3 genes mutations were assessed by immunochemistry and direct sequencing, whilst global gene expression profiling and chromosomal imbalances were determined by microarrays. A full description of the MRI findings at diagnosis and at relapse was integrated with the molecular profiling data and clinical outcome. All DIPG but one were found to harbour either a somatic H3-K27M mutation and/or loss of H3K27 trimethylation. We also discovered a novel K27M mutation in HIST2H3C, and a lysine-to-isoleucine substitution (K27I) in H3F3A, also creating a loss of trimethylation. Patients with tumours harbouring a K27M mutation in H3.3 (H3F3A) did not respond clinically to radiotherapy as well, relapsed significantly earlier and exhibited more metastatic recurrences than those in H3.1 (HIST1H3B/C). H3.3-K27M-mutated DIPG have a proneural/oligodendroglial phenotype and a pro-metastatic gene expression signature with PDGFRA activation, while H3.1-K27M-mutated tumours exhibit a mesenchymal/astrocytic phenotype and a pro-angiogenic/hypoxic signature supported by expression profiling and radiological findings. H3K27 alterations appear as the founding event in DIPG and the mutations in the two main histone H3 variants drive two distinct oncogenic programmes with potential specific therapeutic targets.
authors.affiliation: UMR8203 "Vectorologie et Thérapeutiques Anticancéreuses", CNRS, Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, 94805, Villejuif, France.|Département de Cancérologie de l'Enfant et de l'Adolescent, Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, 94805, Villejuif, France.
authors.forename: David
authors.initials: D
authors.lastname: Castel
authors.affiliation: UMR8203 "Vectorologie et Thérapeutiques Anticancéreuses", CNRS, Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, 94805, Villejuif, France.
authors.forename: Cathy
authors.initials: C
authors.lastname: Philippe
authors.affiliation: Département de Neuroradiologie, INSERM U1000, "Imagerie et Psychiatrie", Hôpital Necker-Enfants Malades, Université Paris V Descartes, Paris, 75015, France.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Calmon
authors.affiliation: UMR8203 "Vectorologie et Thérapeutiques Anticancéreuses", CNRS, Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, 94805, Villejuif, France.
authors.forename: Ludivine
authors.initials: L
authors.lastname: Le Dret
authors.affiliation: UMR8203 "Vectorologie et Thérapeutiques Anticancéreuses", CNRS, Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, 94805, Villejuif, France.
authors.forename: Nathalène
authors.initials: N
authors.lastname: Truffaux
authors.affiliation: Département de Neuroradiologie, INSERM U1000, "Imagerie et Psychiatrie", Hôpital Necker-Enfants Malades, Université Paris V Descartes, Paris, 75015, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.affiliation: Département de Neuropathologie, Hôpital Sainte-Anne, Université Paris V Descartes, Paris, 75014, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Pagès
authors.affiliation: Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK.
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Taylor
authors.affiliation: Département de Biologie et de Pathologie Médicale, Laboratoire de Recherche Translationnelle, Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, Villejuif, 94805, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Saulnier
authors.affiliation: Département de Biologie et de Pathologie Médicale, Laboratoire de Recherche Translationnelle, Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, Villejuif, 94805, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Lacroix
authors.affiliation: Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay
authors.affiliation: Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Jones
authors.affiliation: Département de Neurochirurgie Pédiatrique, Hôpital Necker-Enfants Malades, Université Paris V Descartes, Paris, 75015, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Sainte-Rose
authors.affiliation: Département de Neurochirurgie Pédiatrique, Hôpital Necker-Enfants Malades, Université Paris V Descartes, Paris, 75015, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Blauwblomme
authors.affiliation: Département de Neuropathologie, Hôpital Sainte-Anne, Université Paris V Descartes, Paris, 75014, France.
authors.forename: Felipe
authors.initials: F
authors.lastname: Andreiuolo
authors.affiliation: Département de Neurochirurgie Pédiatrique, Hôpital Necker-Enfants Malades, Université Paris V Descartes, Paris, 75015, France.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Puget
authors.affiliation: UMR8203 "Vectorologie et Thérapeutiques Anticancéreuses", CNRS, Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, 94805, Villejuif, France. jacques.grill@gustaveroussy.fr.|Département de Cancérologie de l'Enfant et de l'Adolescent, Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, 94805, Villejuif, France. jacques.grill@gustaveroussy.fr.
authors.forename: Jacques
authors.initials: J
authors.lastname: Grill
authors.affiliation: Département de Neuropathologie, Hôpital Sainte-Anne, Université Paris V Descartes, Paris, 75014, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Varlet
authors.affiliation: UMR8203 "Vectorologie et Thérapeutiques Anticancéreuses", CNRS, Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, 94805, Villejuif, France. marie-anne.debily@gustaveroussy.fr.|Département de Biologie, Université Evry Val-d'Essonne, 91037, Evry, France. marie-anne.debily@gustaveroussy.fr.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Debily
mesh_terms: D001253:Astrocytes / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D020295:Brain Stem Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005910:Glioma / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D006367:HeLa Cells; D006657:Histones / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D010641:Phenotype; D011149:Pons / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects / Q000601:surgery; D011379:Prognosis
chemical_list: C000609950:H3-3A protein, human; C000609943:H3C2 protein, human; D006657:Histones