The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes.
Studies of paediatric cancers have shown a high frequency of mutation across epigenetic regulators. Here we sequence 633 genes, encoding the majority of known epigenetic regulatory proteins, in over 1,000 paediatric tumours to define the landscape of somatic mutations in epigenetic regulators in paediatric cancer. Our results demonstrate a marked variation in the frequency of gene mutations across 21 different paediatric cancer subtypes, with the highest frequency of mutations detected in high-grade gliomas, T-lineage acute lymphoblastic leukaemia and medulloblastoma, and a paucity of mutations in low-grade glioma and retinoblastoma. The most frequently mutated genes are H3F3A, PHF6, ATRX, KDM6A, SMARCA4, ASXL2, CREBBP, EZH2, MLL2, USP7, ASXL1, NSD2, SETD2, SMC1A and ZMYM3. We identify novel loss-of-function mutations in the ubiquitin-specific processing protease 7 (USP7) in paediatric leukaemia, which result in decreased deubiquitination activity. Collectively, our results help to define the landscape of mutations in epigenetic regulatory genes in paediatric cancer and yield a valuable new database for investigating the role of epigenetic dysregulations in cancer.
1] Department of Computational Biology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA [2].
Robert
R
Huether
1] Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA [2].
Li
L
Dong
Department of Computational Biology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Xiang
X
Chen
Department of Computational Biology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Gang
G
Wu
Department of Computational Biology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Matthew
M
Parker
Department of Computational Biology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Lei
L
Wei
Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Jing
J
Ma
Department of Computational Biology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Michael N
MN
Edmonson
Department of Computational Biology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Erin K
EK
Hedlund
Department of Computational Biology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Michael C
MC
Rusch
Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Sheila A
SA
Shurtleff
The Pediatric Cancer Genome Project Laboratory, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Heather L
HL
Mulder
The Pediatric Cancer Genome Project Laboratory, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Kristy
K
Boggs
The Pediatric Cancer Genome Project Laboratory, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Bhavin
B
Vadordaria
Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Jinjun
J
Cheng
The Pediatric Cancer Genome Project Laboratory, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Donald
D
Yergeau
Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Guangchun
G
Song
Department of Computational Biology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Jared
J
Becksfort
Department of Computational Biology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Gordon
G
Lemmon
Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Catherine
C
Weber
Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Zhongling
Z
Cai
Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Jinjun
J
Dang
Department of Oncology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Michael
M
Walsh
Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Amanda L
AL
Gedman
Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Zachary
Z
Faber
The Pediatric Cancer Genome Project Laboratory, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
John
J
Easton
1] Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA [2] Department of Oncology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Tanja
T
Gruber
Department of Structural Biology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Richard W
RW
Kriwacki
Department of Biochemistry, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Janet F
JF
Partridge
1] The Genome Institute, Washington University School of Medicine, St Louis, Missouri 63108, USA [2] Department of Genetics, Washington University School of Medicine, 4444 Forest Park Ave, St Louis, Missouri 63108, USA [3] Siteman Cancer Center, Washington University, St Louis, Missouri 63108, USA.
Li
L
Ding
1] The Genome Institute, Washington University School of Medicine, St Louis, Missouri 63108, USA [2] Department of Genetics, Washington University School of Medicine, 4444 Forest Park Ave, St Louis, Missouri 63108, USA [3] Siteman Cancer Center, Washington University, St Louis, Missouri 63108, USA.
Richard K
RK
Wilson
1] The Genome Institute, Washington University School of Medicine, St Louis, Missouri 63108, USA [2] Department of Genetics, Washington University School of Medicine, 4444 Forest Park Ave, St Louis, Missouri 63108, USA [3] Siteman Cancer Center, Washington University, St Louis, Missouri 63108, USA.
Elaine R
ER
Mardis
Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Charles G
CG
Mullighan
Department of Developmental Neurobiology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Richard J
RJ
Gilbertson
Department of Developmental Neurobiology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Suzanne J
SJ
Baker
Department of Biochemistry, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Gerard
G
Zambetti
Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
David W
DW
Ellison
Department of Computational Biology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Jinghui
J
Zhang
Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
James R
JR
Downing
D001932:Brain Neoplasms / Q000235:genetics; D002648:Child; D044127:Epigenesis, Genetic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D005809:Genes, Regulator / Q000235:genetics*; D005910:Glioma / Q000235:genetics; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D019572:Retinal Neoplasms / Q000235:genetics; D012175:Retinoblastoma / Q000235:genetics