Novel mutations target distinct subgroups of medulloblastoma.
Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and matched normal blood. One-hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.
St Jude Children's Research Hospital, Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA.
Giles
G
Robinson
Matthew
M
Parker
Tanya A
TA
Kranenburg
Charles
C
Lu
Xiang
X
Chen
Li
L
Ding
Timothy N
TN
Phoenix
Erin
E
Hedlund
Lei
L
Wei
Xiaoyan
X
Zhu
Nader
N
Chalhoub
Suzanne J
SJ
Baker
Robert
R
Huether
Richard
R
Kriwacki
Natasha
N
Curley
Radhika
R
Thiruvenkatam
Jianmin
J
Wang
Gang
G
Wu
Michael
M
Rusch
Xin
X
Hong
Jared
J
Becksfort
Pankaj
P
Gupta
Jing
J
Ma
John
J
Easton
Bhavin
B
Vadodaria
Arzu
A
Onar-Thomas
Tong
T
Lin
Shaoyi
S
Li
Stanley
S
Pounds
Steven
S
Paugh
David
D
Zhao
Daisuke
D
Kawauchi
Martine F
MF
Roussel
David
D
Finkelstein
David W
DW
Ellison
Ching C
CC
Lau
Eric
E
Bouffet
Tim
T
Hassall
Sridharan
S
Gururangan
Richard
R
Cohn
Robert S
RS
Fulton
Lucinda L
LL
Fulton
David J
DJ
Dooling
Kerri
K
Ochoa
Amar
A
Gajjar
Elaine R
ER
Mardis
Richard K
RK
Wilson
James R
JR
Downing
Jinghui
J
Zhang
Richard J
RJ
Gilbertson
D000818:Animals; D015703:Antigens, CD; D050882:CREB-Binding Protein / Q000235:genetics; D015820:Cadherins / Q000235:genetics; D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000235:genetics; D019070:Cell Lineage; D002528:Cerebellar Neoplasms / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D002648:Child; D058534:Class I Phosphatidylinositol 3-Kinases; D053487:DEAD-box RNA Helicases / Q000235:genetics; D056915:DNA Copy Number Variations; D004265:DNA Helicases / Q000235:genetics; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D015894:Genome, Human / Q000235:genetics; D023281:Genomics; D053823:Hedgehog Proteins / Q000378:metabolism; D056466:Histone Demethylases / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D008527:Medulloblastoma / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D008745:Methylation; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics
D015703:Antigens, CD; D050882:CREB-Binding Protein; D015820:Cadherins; D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins; D058534:Class I Phosphatidylinositol 3-Kinases; D053487:DEAD-box RNA Helicases; D004265:DNA Helicases; D053823:Hedgehog Proteins; D056466:Histone Demethylases; D006657:Histones; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; C513384:CDH1 protein, human; C495270:CTNNB1 protein, human; C577585:Fzr1 protein, mouse; C509239:SHH protein, human; C102796:ZMYM3 protein, human; C523998:KDM6A protein, human; C494363:CREBBP protein, human; C484760:PIK3CA protein, human; C119332:DDX3X protein, human; C084108:SMARCA4 protein, human