Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations.
Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.
1] Division of Pathology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. [2] Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. [3] Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. [4].
Pawel
P
Buczkowicz
1] Division of Pediatric Hematology/Oncology, Duke University Medical Center, Durham, North Carolina, USA. [2].
Christine
C
Hoeman
1] Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Patricia
P
Rakopoulos
Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
Sanja
S
Pajovic
Génome Québec Innovation Centre, McGill University, Montreal, Quebec, Canada.
Louis
L
Letourneau
Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.
Misko
M
Dzamba
Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
Andrew
A
Morrison
Laboratory of Chromatin Biology and Epigenetics, Rockefeller University, New York, New York, USA.
Peter
P
Lewis
Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Eric
E
Bouffet
Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Ute
U
Bartels
Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
Jennifer
J
Zuccaro
Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
Sameer
S
Agnihotri
Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
Scott
S
Ryall
1] Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Mark
M
Barszczyk
1] Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Yevgen
Y
Chornenkyy
Génome Québec Innovation Centre, McGill University, Montreal, Quebec, Canada.
Mathieu
M
Bourgey
Génome Québec Innovation Centre, McGill University, Montreal, Quebec, Canada.
Guillaume
G
Bourque
Génome Québec Innovation Centre, McGill University, Montreal, Quebec, Canada.
Alexandre
A
Montpetit
Division of Pediatric Hematology/Oncology, Duke University Medical Center, Durham, North Carolina, USA.
Francisco
F
Cordero
Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
Pedro
P
Castelo-Branco
Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
Joshua
J
Mangerel
1] Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Uri
U
Tabori
Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
King Ching
KC
Ho
1] Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Annie
A
Huang
Division of Cancer Therapeutics, Institute of Cancer Research, London, UK.
Kathryn R
KR
Taylor
Division of Cancer Therapeutics, Institute of Cancer Research, London, UK.
Alan
A
Mackay
Department of Pediatric Hematology-Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota, USA.
Anne E
AE
Bendel
Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA.
Javad
J
Nazarian
Department of Pediatrics-Hematology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
Jason R
JR
Fangusaro
Division of Pediatric Hematology/Oncology and Neuropathology, New York University Cancer Institute, New York University Langone Medical Center, New York, New York, USA.
Matthias A
MA
Karajannis
Division of Pediatric Hematology/Oncology and Neuropathology, New York University Cancer Institute, New York University Langone Medical Center, New York, New York, USA.
David
D
Zagzag
Department of Pediatrics, Children's Hospital Colorado, Denver, Colorado, USA.
Nicholas K
NK
Foreman
Department of Pediatrics, Children's Hospital Colorado, Denver, Colorado, USA.
Andrew
A
Donson
Department of Pathology, Arnold Palmer Hospital for Children, Orlando, Florida, USA.
Julia V
JV
Hegert
Department of Pathology, Arnold Palmer Hospital for Children, Orlando, Florida, USA.
Amy
A
Smith
Clark H. Smith Brain Tumour Centre, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
Jennifer
J
Chan
Clark H. Smith Brain Tumour Centre, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
Lucy
L
Lafay-Cousin
Department of Pediatric Neurology and Neuro-Oncology, BC Children's Hospital, Vancouver, British Columbia, Canada.
Sandra
S
Dunn
Department of Pediatric Neurology and Neuro-Oncology, BC Children's Hospital, Vancouver, British Columbia, Canada.
Juliette
J
Hukin
Department of Pediatric Neurology and Neuro-Oncology, BC Children's Hospital, Vancouver, British Columbia, Canada.
Chris
C
Dunham
Division of Hematology/Oncology, McMaster Children's Hospital, Hamilton, Ontario, Canada.
Katrin
K
Scheinemann
Department of Pathology and Laboratory Medicine, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
Jean
J
Michaud
Department of Hematology/Oncology, Children's Hospital London Health Sciences Centre, London, Ontario, Canada.
Shayna
S
Zelcer
Department of Hematology/Oncology, Children's Hospital London Health Sciences Centre, London, Ontario, Canada.
David
D
Ramsay
Monash Institute of Medical Research, Monash Medical Centre, Clayton, Victoria, Australia.
Jason
J
Cain
Department of Neurological Surgery, Weill Cornell Medical College and Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Cameron
C
Brennan
Department of Neurological Surgery, Weill Cornell Medical College and Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Mark M
MM
Souweidane
Division of Cancer Therapeutics, Institute of Cancer Research, London, UK.
Chris
C
Jones
Laboratory of Chromatin Biology and Epigenetics, Rockefeller University, New York, New York, USA.
C David
CD
Allis
1] Department of Computer Science, University of Toronto, Toronto, Ontario, Canada. [2] The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
Michael
M
Brudno
1] Division of Pediatric Hematology/Oncology, Duke University Medical Center, Durham, North Carolina, USA. [2].
Oren
O
Becher
1] Division of Pathology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. [2] Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. [3] Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. [4].
Cynthia
C
Hawkins
D030201:Activin Receptors, Type I / Q000235:genetics*; D000818:Animals; D020295:Brain Stem Neoplasms / Q000145:classification / Q000235:genetics*; D002648:Child; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D005910:Glioma / Q000145:classification / Q000235:genetics*; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism; D051797:Inhibitor of Differentiation Protein 2 / Q000378:metabolism; D010766:Phosphorylation; D017422:Sequence Analysis, DNA; D051785:Smad Proteins / Q000378:metabolism; D015027:Zebrafish
C497453:ID1 protein, human; C497450:ID2 protein, human; D051798:Inhibitor of Differentiation Protein 1; D051797:Inhibitor of Differentiation Protein 2; D051785:Smad Proteins; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I