title: Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma.
abstract: Diffuse Intrinsic Pontine Gliomas (DIPGs) are deadly paediatric brain tumours where needle biopsies help guide diagnosis and targeted therapies. To address spatial heterogeneity, here we analyse 134 specimens from various neuroanatomical structures of whole autopsy brains from nine DIPG patients. Evolutionary reconstruction indicates histone 3 (H3) K27M--including H3.2K27M--mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumour and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis. These H3K27M ubiquitously-associated mutations involve alterations in TP53 cell-cycle (TP53/PPM1D) or specific growth factor pathways (ACVR1/PIK3R1). Later oncogenic alterations arise in sub-clones and often affect the PI3K pathway. Our findings are consistent with early tumour spread outside the brainstem including the cerebrum. The spatial and temporal homogeneity of main driver mutations in DIPG implies they will be captured by limited biopsies and emphasizes the need to develop therapies specifically targeting obligate oncohistone partnerships.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Québec, Canada H3A 1B1.|McGill University and Génome Québec Innovation Centre, Montreal, Québec, Canada H3A 0G1.
authors.forename: Hamid
authors.initials: H
authors.lastname: Nikbakht
authors.affiliation: Research Center for Genetic Medicine, Children's National Health System, Washington, District Of Columbia 20010, USA.|Institute for Biomedical Sciences, George Washington University School of Medicine and Health Sciences, Washington, District Of Columbia 20052, USA.
authors.forename: Eshini
authors.initials: E
authors.lastname: Panditharatna
authors.affiliation: Department of Pediatrics, McGill University and McGill University Heath Centre Research Institute, Montreal, Québec, Canada H4A 3J1.
authors.forename: Leonie G
authors.initials: LG
authors.lastname: Mikael
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Québec, Canada H3A 1B1.|McGill University and Génome Québec Innovation Centre, Montreal, Québec, Canada H3A 0G1.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Québec, Canada H3A 1B1.
authors.forename: Tenzin
authors.initials: T
authors.lastname: Gayden
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Québec, Canada H3A 1B1.|McGill University and Génome Québec Innovation Centre, Montreal, Québec, Canada H3A 0G1.
authors.forename: Matthew
authors.initials: M
authors.lastname: Osmond
authors.affiliation: Division of Pathology, Children's National Health System, Washington, District Of Columbia 20010, USA.
authors.forename: Cheng-Ying
authors.initials: CY
authors.lastname: Ho
authors.affiliation: Research Center for Genetic Medicine, Children's National Health System, Washington, District Of Columbia 20010, USA.
authors.forename: Madhuri
authors.initials: M
authors.lastname: Kambhampati
authors.affiliation: Center for Cancer and Blood Disorders, Children's National Health System, Washington, District Of Columbia 20010, USA.
authors.forename: Eugene I
authors.initials: EI
authors.lastname: Hwang
authors.affiliation: Department of Pediatrics, McGill University and McGill University Heath Centre Research Institute, Montreal, Québec, Canada H4A 3J1.
authors.forename: Damien
authors.initials: D
authors.lastname: Faury
authors.affiliation: The Department of Neurological Surgery, George Washington University School of Medicine and Health Sciences, Washington, District Of Columbia 20052, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Siu
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Québec, Canada H3A 1B1.|McGill University and Génome Québec Innovation Centre, Montreal, Québec, Canada H3A 0G1.
authors.forename: Simon
authors.initials: S
authors.lastname: Papillon-Cavanagh
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Québec, Canada H3A 1B1.
authors.forename: Denise
authors.initials: D
authors.lastname: Bechet
authors.affiliation: Center for Molecular Oncologic Pathology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusett 02115, USA.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
authors.affiliation: Department of Pathology, CHU Ste-Justine, Université de Montréal, Montreal, Québec, Canada H3T 1C5.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ellezam
authors.affiliation: UQ Child Health Research Centre, The University of Queensland, Brisbane, Queensland 4101, Australia.
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Ingram
authors.affiliation: University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Queensland 4102, Australia.
authors.forename: Caedyn
authors.initials: C
authors.lastname: Stinson
authors.affiliation: UQ Child Health Research Centre, The University of Queensland, Brisbane, Queensland 4101, Australia.|University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Queensland 4102, Australia.|Oncology Service, Children's Health Queensland Hospital and Health Service, Brisbane, Queensland 4101, Australia.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Moore
authors.affiliation: National Cancer Institute, National Institute of Health, Bethesda, Maryland 20892, USA.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Warren
authors.affiliation: Department of Pathology, Montreal Neurological Hospital, McGill University, Montreal, Québec, Canada H3A 2B4.
authors.forename: Jason
authors.initials: J
authors.lastname: Karamchandani
authors.affiliation: Brain Tumour Institute, Center for Neuroscience and Behavioral Medicine, Children's National Health System, Washington, District Of Columbia, 20010, USA.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Packer
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Québec, Canada H3A 1B1.|Department of Pediatrics, McGill University and McGill University Heath Centre Research Institute, Montreal, Québec, Canada H4A 3J1.
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Québec, Canada H3A 1B1.|McGill University and Génome Québec Innovation Centre, Montreal, Québec, Canada H3A 0G1.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Research Center for Genetic Medicine, Children's National Health System, Washington, District Of Columbia 20010, USA.|Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, District Of Columbia 20052, USA.
authors.forename: Javad
authors.initials: J
authors.lastname: Nazarian
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism; D001344:Autopsy; D001931:Brain Mapping; D001933:Brain Stem / Q000378:metabolism / Q000473:pathology; D020295:Brain Stem Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D054022:Cerebrum / Q000378:metabolism / Q000473:pathology; D002648:Child; D058543:Class Ia Phosphatidylinositol 3-Kinase; D060965:Clonal Evolution; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D000071636:Protein Phosphatase 2C; D015398:Signal Transduction; D013238:Stereotaxic Techniques; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D030201:Activin Receptors, Type I; D058543:Class Ia Phosphatidylinositol 3-Kinase; D006657:Histones; D019869:Phosphatidylinositol 3-Kinases; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C; D016159:Tumor Suppressor Protein p53; C495901:TP53 protein, human; C588001:PIK3R1 protein, human; C425423:ACVR1 protein, human; C000607458:PPM1D protein, human