Novel mutations target distinct subgroups of medulloblastoma

Giles Robinson, Matthew Parker, Tanya A. Kranenburg, Charles Lu, Xiang Chen, Li Ding, Timothy N. Phoenix, Erin Hedlund, Lei Wei, Xiaoyan Zhu, Nader Chalhoub, Suzanne J. Baker, Robert Huether, Richard Kriwacki, Natasha Curley, Radhika Thiruvenkatam, Jianmin Wang, Gang Wu, Michael Rusch, Xin Hong, Jared Becksfort, Pankaj Gupta, Jing Ma, John Easton, Bhavin Vadodaria, Arzu Onar-Thomas, Tong Lin, Shaoyi Li, Stanley Pounds, Steven Paugh, David Zhao, Daisuke Kawauchi, Martine F. Roussel, David Finkelstein, David W. Ellison, Ching C. Lau, Eric Bouffet, Tim Hassall, Sridharan Gururangan, Richard Cohn, Robert S. Fulton, Lucinda L. Fulton, David J. Dooling, Kerri Ochoa, Amar Gajjar, Elaine R. Mardis, Richard K. Wilson, James R. Downing, Jinghui Zhang () and Richard J. Gilbertson ()
Additional contact information
Giles Robinson: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Matthew Parker: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Tanya A. Kranenburg: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Charles Lu: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Xiang Chen: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Li Ding: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Timothy N. Phoenix: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Erin Hedlund: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Lei Wei: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Xiaoyan Zhu: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Nader Chalhoub: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Suzanne J. Baker: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Robert Huether: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Richard Kriwacki: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Natasha Curley: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Radhika Thiruvenkatam: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Jianmin Wang: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Gang Wu: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Michael Rusch: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Xin Hong: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Jared Becksfort: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Pankaj Gupta: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Jing Ma: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
John Easton: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Bhavin Vadodaria: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Arzu Onar-Thomas: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Tong Lin: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Shaoyi Li: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Stanley Pounds: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Steven Paugh: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
David Zhao: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Daisuke Kawauchi: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Martine F. Roussel: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
David Finkelstein: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
David W. Ellison: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Ching C. Lau: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Eric Bouffet: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Tim Hassall: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Sridharan Gururangan: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Richard Cohn: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Robert S. Fulton: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Lucinda L. Fulton: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
David J. Dooling: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Kerri Ochoa: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Amar Gajjar: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Elaine R. Mardis: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Richard K. Wilson: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
James R. Downing: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Jinghui Zhang: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
Richard J. Gilbertson: St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project

Nature, 2012, vol. 488, issue 7409, 43-48

Abstract: Abstract 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.

Date: 2012
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DOI: 10.1038/nature11213

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