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

Author

Listed:
  • 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
    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
    Washington University School of Medicine
    Siteman Cancer Center, Washington University)

  • Richard K. Wilson

    (The Genome Institute, Washington University School of Medicine
    Washington University School of Medicine
    Siteman Cancer Center, Washington University)

  • Elaine R. Mardis

    (The Genome Institute, Washington University School of Medicine
    Washington University School of Medicine
    Siteman Cancer Center, Washington University)

  • 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)

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.

Suggested Citation

  • 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, 2014. "The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes," Nature Communications, Nature, vol. 5(1), pages 1-7, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4630
    DOI: 10.1038/ncomms4630
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    Cited by:

    1. Lele Song & Qinglan Li & Lingbo Xia & Arushi Eesha Sahay & Qi Qiu & Yuanyuan Li & Haitao Li & Kotaro Sasaki & Katalin Susztak & Hao Wu & Liling Wan, 2024. "Single-cell multiomics reveals ENL mutation perturbs kidney developmental trajectory by rewiring gene regulatory landscape," Nature Communications, Nature, vol. 15(1), pages 1-26, December.
    2. Alexandra D’Oto & Jie Fang & Hongjian Jin & Beisi Xu & Shivendra Singh & Anoushka Mullasseril & Victoria Jones & Ahmed Abu-Zaid & Xinyu Buttlar & Bailey Cooke & Dongli Hu & Jason Shohet & Andrew J. Mu, 2021. "KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma," Nature Communications, Nature, vol. 12(1), pages 1-19, December.

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