Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma.
Pediatric midline high-grade astrocytomas (mHGAs) are incurable with few treatment targets identified. Most tumors harbor mutations encoding p.Lys27Met in histone H3 variants. In 40 treatment-naive mHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with histone H3.1 p.Lys27Met substitution, whereas FGFR1 mutations or fusions occur in thalamic tumors associated with histone H3.3 p.Lys27Met substitution. Hyperactivation of the bone morphogenetic protein (BMP)-ACVR1 developmental pathway in mHGAs harboring ACVR1 mutations led to increased levels of phosphorylated SMAD1, SMAD5 and SMAD8 and upregulation of BMP downstream early-response genes in tumor cells. Global DNA methylation profiles were significantly associated with the p.Lys27Met alteration, regardless of the mutant histone H3 variant and irrespective of tumor location, supporting the role of this substitution in driving the epigenetic phenotype. This work considerably expands the number of potential treatment targets and further justifies pretreatment biopsy in pediatric mHGA as a means to orient therapeutic efforts in this disease.
1] Division of Experimental Medicine, Montreal Children's Hospital, McGill University and McGill University Health Centre, Montreal, Quebec, Canada. [2].
Adam M
AM
Fontebasso
1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [2].
Simon
S
Papillon-Cavanagh
1] Wellcome Trust Sanger Institute, Hinxton, UK. [2].
Jeremy
J
Schwartzentruber
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
Hamid
H
Nikbakht
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
Noha
N
Gerges
Department of Pathology, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.
Pierre-Olivier
PO
Fiset
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
Denise
D
Bechet
1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [2] Department of Pediatrics, McGill University, Montreal, Quebec, Canada.
Damien
D
Faury
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
Nicolas
N
De Jay
Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Lori A
LA
Ramkissoon
Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Aoife
A
Corcoran
Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
David T W
DT
Jones
Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Dominik
D
Sturm
Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Pascal
P
Johann
Department of Neurological Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, Illinois, USA.
Tadanori
T
Tomita
Department of Pediatrics Hematology-Oncology, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, Illinois, USA.
Stewart
S
Goldman
Clinical Pediatric Neurosurgical Oncology, Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, USA.
Mahmoud
M
Nagib
Department of Pediatric Hematology-Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota, USA.
Anne
A
Bendel
1] Department of Neurosurgery, Boston Children's Hospital, Boston, Massachusetts, USA. [2] Harvard Medical School, Boston, Massachusetts, USA.
Liliana
L
Goumnerova
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Daniel C
DC
Bowers
Department of Neurological Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA.
Jeffrey R
JR
Leonard
Department of Pediatrics, Hematology-Oncology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA.
Joshua B
JB
Rubin
Department of Neurological Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, Illinois, USA.
Tord
T
Alden
Department of Neurosurgery, Seattle Children's Hospital, Seattle, Washington, USA.
Samuel
S
Browd
Cancer and Blood Disorders Center, Seattle Children's Hospital, Seattle, Washington, USA.
J Russell
JR
Geyer
Cancer and Blood Disorders Center, Seattle Children's Hospital, Seattle, Washington, USA.
Sarah
S
Leary
Department of Neurological Surgery, Johns Hopkins Hospital, Baltimore, Maryland, USA.
George
G
Jallo
Department of Pediatric Hematology-Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.
Kenneth
K
Cohen
Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
Nalin
N
Gupta
Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
Michael D
MD
Prados
Department of Hematology-Oncology, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada.
Anne-Sophie
AS
Carret
Department of Pathology, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada.
Benjamin
B
Ellezam
Department of Neurosurgery, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada.
Louis
L
Crevier
Department of Neurosurgery, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.
Almos
A
Klekner
Department of Neurosurgery, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.
Laszlo
L
Bognar
2nd Department of Paediatrics, Semmelweis University, Budapest, Hungary.
Peter
P
Hauser
2nd Department of Paediatrics, Semmelweis University, Budapest, Hungary.
Miklos
M
Garami
Department of Neurosurgery, Children's National Medical Center, Washington, DC, USA.
John
J
Myseros
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
Zhifeng
Z
Dong
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
Peter M
0000000255686586
PM
Siegel
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Hayley
H
Malkin
1] Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Azra H
AH
Ligon
Department of Pathology, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.
Steffen
S
Albrecht
Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Stefan M
SM
Pfister
1] Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA. [4] Department of Pathology, Boston Children's Hospital, Boston, Massachusetts, USA. [5].
Keith L
KL
Ligon
1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [2].
Jacek
J
Majewski
1] Division of Experimental Medicine, Montreal Children's Hospital, McGill University and McGill University Health Centre, Montreal, Quebec, Canada. [2] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [3] Department of Pediatrics, McGill University, Montreal, Quebec, Canada. [4].
Nada
N
Jabado
1] Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [3] Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA. [4].
Mark W
MW
Kieran
D030201:Activin Receptors, Type I / Q000235:genetics*; D000818:Animals; D001254:Astrocytoma / Q000235:genetics*; D001483:Base Sequence; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics*; D002648:Child; D056915:DNA Copy Number Variations / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D017422:Sequence Analysis, DNA; D051785:Smad Proteins / Q000378:metabolism
D019485:Bone Morphogenetic Proteins; D051785:Smad Proteins; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I