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Novel mutations target distinct subgroups of medulloblastoma

Author

Listed:
  • Giles Robinson

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital
    St Jude Children’s Research Hospital)

  • Matthew Parker

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Tanya A. Kranenburg

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Charles Lu

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    The Genome Institute, Washington University School of Medicine in St Louis)

  • Xiang Chen

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Li Ding

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    The Genome Institute, Washington University School of Medicine in St Louis
    Washington University School of Medicine in St Louis)

  • Timothy N. Phoenix

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Erin Hedlund

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Lei Wei

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital
    St Jude Children’s Research Hospital)

  • Xiaoyan Zhu

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Nader Chalhoub

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Suzanne J. Baker

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Robert Huether

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital
    St Jude Children’s Research Hospital)

  • Richard Kriwacki

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Natasha Curley

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Radhika Thiruvenkatam

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Jianmin Wang

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Gang Wu

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Michael Rusch

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Xin Hong

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    The Genome Institute, Washington University School of Medicine in St Louis)

  • Jared Becksfort

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Pankaj Gupta

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Jing Ma

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • John Easton

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Bhavin Vadodaria

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Arzu Onar-Thomas

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Tong Lin

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Shaoyi Li

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Stanley Pounds

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Steven Paugh

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • David Zhao

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Daisuke Kawauchi

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Martine F. Roussel

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • David Finkelstein

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • David W. Ellison

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Ching C. Lau

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    Texas Children’s Cancer and Hematology Centers, 6701 Fannin Street, Ste. 1420, Houston, Texas 77030, USA)

  • Eric Bouffet

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada)

  • Tim Hassall

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    The Royal Children’s Hospital, 50 Flemington Road)

  • Sridharan Gururangan

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    Duke University Medical Center, 102382)

  • Richard Cohn

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    The School of Women’s and Children’s Health, University of New South Wales)

  • Robert S. Fulton

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    The Genome Institute, Washington University School of Medicine in St Louis
    Washington University School of Medicine in St Louis)

  • Lucinda L. Fulton

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    The Genome Institute, Washington University School of Medicine in St Louis
    Washington University School of Medicine in St Louis)

  • David J. Dooling

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    The Genome Institute, Washington University School of Medicine in St Louis
    Washington University School of Medicine in St Louis)

  • Kerri Ochoa

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    The Genome Institute, Washington University School of Medicine in St Louis
    Washington University School of Medicine in St Louis)

  • Amar Gajjar

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Elaine R. Mardis

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    The Genome Institute, Washington University School of Medicine in St Louis
    Washington University School of Medicine in St Louis
    Siteman Cancer Center, Washington University School of Medicine in St Louis)

  • Richard K. Wilson

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    The Genome Institute, Washington University School of Medicine in St Louis
    Washington University School of Medicine in St Louis
    Washington University School of Medicine in St Louis)

  • James R. Downing

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Jinghui Zhang

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital)

  • Richard J. Gilbertson

    (St Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project
    St Jude Children’s Research Hospital
    St Jude Children’s Research Hospital)

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.

Suggested Citation

  • 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 Hueth, 2012. "Novel mutations target distinct subgroups of medulloblastoma," Nature, Nature, vol. 488(7409), pages 43-48, August.
    • Handle: RePEc:nat:nature:v:488:y:2012:i:7409:d:10.1038_nature11213
    DOI: 10.1038/nature11213
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    Citations

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    Cited by:

    1. Elizabeth J. Radford & Hong-Kee Tan & Malin H. L. Andersson & James D. Stephenson & Eugene J. Gardner & Holly Ironfield & Andrew J. Waters & Daniel Gitterman & Sarah Lindsay & Federico Abascal & Iñigo, 2023. "Saturation genome editing of DDX3X clarifies pathogenicity of germline and somatic variation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Michelle M. Kameda-Smith & Helen Zhu & En-Ching Luo & Yujin Suk & Agata Xella & Brian Yee & Chirayu Chokshi & Sansi Xing & Frederick Tan & Raymond G. Fox & Ashley A. Adile & David Bakhshinyan & Kevin , 2022. "Characterization of an RNA binding protein interactome reveals a context-specific post-transcriptional landscape of MYC-amplified medulloblastoma," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Zaili Luo & Dazhuan Xin & Yunfei Liao & Kalen Berry & Sean Ogurek & Feng Zhang & Liguo Zhang & Chuntao Zhao & Rohit Rao & Xinran Dong & Hao Li & Jianzhong Yu & Yifeng Lin & Guoying Huang & Lingli Xu &, 2023. "Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    4. Samuel Rivero-Hinojosa & Melanie Grant & Aswini Panigrahi & Huizhen Zhang & Veronika Caisova & Catherine M. Bollard & Brian R. Rood, 2021. "Proteogenomic discovery of neoantigens facilitates personalized multi-antigen targeted T cell immunotherapy for brain tumors," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    5. Jasmin Bartl & Marco Zanini & Flavia Bernardi & Antoine Forget & Lena Blümel & Julie Talbot & Daniel Picard & Nan Qin & Gabriele Cancila & Qingsong Gao & Soumav Nath & Idriss Mahoungou Koumba & Mariet, 2022. "The HHIP-AS1 lncRNA promotes tumorigenicity through stabilization of dynein complex 1 in human SHH-driven tumors," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    6. Suijuan Zhong & Mengdi Wang & Luwei Huang & Youqiao Chen & Yuxin Ge & Jiyao Zhang & Yingchao Shi & Hao Dong & Xin Zhou & Bosong Wang & Tian Lu & Xiaoxi Jing & Yufeng Lu & Junjing Zhang & Xiaoqun Wang , 2023. "Single-cell epigenomics and spatiotemporal transcriptomics reveal human cerebellar development," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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