The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma.
Pediatric high-grade glioma (HGG) is a devastating disease with a less than 20% survival rate 2 years after diagnosis. We analyzed 127 pediatric HGGs, including diffuse intrinsic pontine gliomas (DIPGs) and non-brainstem HGGs (NBS-HGGs), by whole-genome, whole-exome and/or transcriptome sequencing. We identified recurrent somatic mutations in ACVR1 exclusively in DIPGs (32%), in addition to previously reported frequent somatic mutations in histone H3 genes, TP53 and ATRX, in both DIPGs and NBS-HGGs. Structural variants generating fusion genes were found in 47% of DIPGs and NBS-HGGs, with recurrent fusions involving the neurotrophin receptor genes NTRK1, NTRK2 and NTRK3 in 40% of NBS-HGGs in infants. Mutations targeting receptor tyrosine kinase-RAS-PI3K signaling, histone modification or chromatin remodeling, and cell cycle regulation were found in 68%, 73% and 59% of pediatric HGGs, respectively, including in DIPGs and NBS-HGGs. This comprehensive analysis provides insights into the unique and shared pathways driving pediatric HGG within and outside the brainstem.
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Gang
G
Wu
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105.|Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN 38163.
Alexander K
AK
Diaz
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Barbara S
BS
Paugh
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Sherri L
SL
Rankin
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105.
Bensheng
B
Ju
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Yongjin
Y
Li
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Xiaoyan
X
Zhu
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Chunxu
C
Qu
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Xiang
X
Chen
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Junyuan
J
Zhang
Department of Pediatric Cancer Genome Project, St. Jude Children's Research Hospital, Memphis, TN 38105.
John
J
Easton
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Michael
M
Edmonson
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Xiaotu
X
Ma
The Genome Institute, Washington University, 633108.
Charles
C
Lu
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Panduka
P
Nagahawatte
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Erin
E
Hedlund
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Michael
M
Rusch
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105.
Stanley
S
Pounds
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105.
Tong
T
Lin
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105.
Arzu
A
Onar-Thomas
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Robert
R
Huether
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Richard
R
Kriwacki
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Matthew
M
Parker
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Pankaj
P
Gupta
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Jared
J
Becksfort
Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY 14263.
Lei
L
Wei
Department of Pediatric Cancer Genome Project, St. Jude Children's Research Hospital, Memphis, TN 38105.
Heather L
HL
Mulder
Department of Pediatric Cancer Genome Project, St. Jude Children's Research Hospital, Memphis, TN 38105.
Kristy
K
Boggs
Department of Pediatric Cancer Genome Project, St. Jude Children's Research Hospital, Memphis, TN 38105.
Bhavin
B
Vadodaria
Department of Pediatric Cancer Genome Project, St. Jude Children's Research Hospital, Memphis, TN 38105.
Donald
D
Yergeau
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Jake C
JC
Russell
The Genome Institute, Washington University, 633108.
Kerri
K
Ochoa
The Genome Institute, Washington University, 633108.
Robert S
RS
Fulton
The Genome Institute, Washington University, 633108.
Lucinda L
LL
Fulton
Division of Molecular Pathology, Institute for Cancer Research, London, UK SM2 5NG.|Division of Cancer Therapeutics, Institute for Cancer Research, London, UK SM2 5NG.
Chris
C
Jones
Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN 38105.
Frederick A
FA
Boop
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Alberto
A
Broniscer
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Cynthia
C
Wetmore
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Amar
A
Gajjar
The Genome Institute, Washington University, 633108.
Li
L
Ding
The Genome Institute, Washington University, 633108.
Elaine R
ER
Mardis
The Genome Institute, Washington University, 633108.
Richard K
RK
Wilson
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105.
Michael R
MR
Taylor
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105.
James R
JR
Downing
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105.
David W
DW
Ellison
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Jinghui
J
Zhang
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105.|Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN 38163.
Suzanne J
SJ
Baker
D030201:Activin Receptors, Type I / Q000235:genetics*; D000818:Animals; D020295:Brain Stem Neoplasms / Q000235:genetics*; D002648:Child; D015331:Cohort Studies; D019295:Computational Biology; D020869:Gene Expression Profiling; D050939:Gene Fusion / Q000235:genetics; D005910:Glioma / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D046228:Microarray Analysis; D020917:Receptor, trkA / Q000235:genetics; D020813:Receptor, trkB / Q000235:genetics; D020812:Receptor, trkC / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics*; D018709:Statistics, Nonparametric; D015027:Zebrafish
D020917:Receptor, trkA; D020813:Receptor, trkB; D020812:Receptor, trkC; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I