The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes

Robert Huether, Li Dong, Xiang Chen, Gang Wu, Matthew Parker, Lei Wei, Jing Ma, Michael N. Edmonson, Erin K. Hedlund, Michael C. Rusch, Sheila A. Shurtleff, Heather L. Mulder, Kristy Boggs, Bhavin Vadordaria, Jinjun Cheng, Donald Yergeau, Guangchun Song, Jared Becksfort, Gordon Lemmon, Catherine Weber, Zhongling Cai, Jinjun Dang, Michael Walsh, Amanda L. Gedman, Zachary Faber, John Easton, Tanja Gruber, Richard W. Kriwacki, Janet F. Partridge, Li Ding, Richard K. Wilson, Elaine R. Mardis, Charles G. Mullighan, Richard J. Gilbertson, Suzanne J. Baker, Gerard Zambetti, David W. Ellison, Jinghui Zhang () and James R. Downing ()
Additional contact information
Robert Huether: St Jude Children’s Research Hospital
Li Dong: St Jude Children’s Research Hospital
Xiang Chen: St Jude Children’s Research Hospital
Gang Wu: St Jude Children’s Research Hospital
Matthew Parker: St Jude Children’s Research Hospital
Lei Wei: St Jude Children’s Research Hospital
Jing Ma: St Jude Children’s Research Hospital
Michael N. Edmonson: St Jude Children’s Research Hospital
Erin K. Hedlund: St Jude Children’s Research Hospital
Michael C. Rusch: St Jude Children’s Research Hospital
Sheila A. Shurtleff: St Jude Children’s Research Hospital
Heather L. Mulder: The Pediatric Cancer Genome Project Laboratory, St Jude Children’s Research Hospital
Kristy Boggs: The Pediatric Cancer Genome Project Laboratory, St Jude Children’s Research Hospital
Bhavin Vadordaria: The Pediatric Cancer Genome Project Laboratory, St Jude Children’s Research Hospital
Jinjun Cheng: St Jude Children’s Research Hospital
Donald Yergeau: The Pediatric Cancer Genome Project Laboratory, St Jude Children’s Research Hospital
Guangchun Song: St Jude Children’s Research Hospital
Jared Becksfort: St Jude Children’s Research Hospital
Gordon Lemmon: St Jude Children’s Research Hospital
Catherine Weber: St Jude Children’s Research Hospital
Zhongling Cai: St Jude Children’s Research Hospital
Jinjun Dang: St Jude Children’s Research Hospital
Michael Walsh: St Jude Children’s Research Hospital
Amanda L. Gedman: St Jude Children’s Research Hospital
Zachary Faber: St Jude Children’s Research Hospital
John Easton: The Pediatric Cancer Genome Project Laboratory, St Jude Children’s Research Hospital
Tanja Gruber: St Jude Children’s Research Hospital
Richard W. Kriwacki: St Jude Children’s Research Hospital
Janet F. Partridge: St Jude Children’s Research Hospital
Li Ding: The Genome Institute, Washington University School of Medicine
Richard K. Wilson: The Genome Institute, Washington University School of Medicine
Elaine R. Mardis: The Genome Institute, Washington University School of Medicine
Charles G. Mullighan: St Jude Children’s Research Hospital
Richard J. Gilbertson: St Jude Children’s Research Hospital
Suzanne J. Baker: St Jude Children’s Research Hospital
Gerard Zambetti: St Jude Children’s Research Hospital
David W. Ellison: St Jude Children’s Research Hospital
Jinghui Zhang: St Jude Children’s Research Hospital
James R. Downing: St Jude Children’s Research Hospital

Nature Communications, 2014, vol. 5, issue 1, 1-7

Abstract: Abstract 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.

Date: 2014
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DOI: 10.1038/ncomms4630

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