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The whole-genome landscape of medulloblastoma subtypes

Author

Listed:
  • Paul A. Northcott

    (German Cancer Research Center (DKFZ)
    St Jude Children’s Research Hospital)

  • Ivo Buchhalter

    (German Cancer Research Center (DKFZ)
    German Cancer Research Center (DKFZ)
    Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University)

  • A. Sorana Morrissy

    (Developmental & Stem Cell Biology Program, The Hospital for Sick Children)

  • Volker Hovestadt

    (German Cancer Research Center (DKFZ))

  • Joachim Weischenfeldt

    (Biotech Research & Innovation Centre (BRIC), Copenhagen University and Finsen Laboratory)

  • Tobias Ehrenberger

    (Massachusetts Institute of Technology)

  • Susanne Gröbner

    (German Cancer Research Center (DKFZ)
    German Cancer Consortium (DKTK))

  • Maia Segura-Wang

    (Genome Biology Unit, European Molecular Biology Laboratory (EMBL))

  • Thomas Zichner

    (Genome Biology Unit, European Molecular Biology Laboratory (EMBL))

  • Vasilisa A. Rudneva

    (St Jude Children’s Research Hospital
    Genome Biology Unit, European Molecular Biology Laboratory (EMBL))

  • Hans-Jörg Warnatz

    (Max Planck Institute for Molecular Genetics)

  • Nikos Sidiropoulos

    (Biotech Research & Innovation Centre (BRIC), Copenhagen University and Finsen Laboratory)

  • Aaron H. Phillips

    (St Jude Children’s Research Hospital)

  • Steven Schumacher

    (Broad Institute of Harvard and MIT)

  • Kortine Kleinheinz

    (German Cancer Research Center (DKFZ))

  • Sebastian M. Waszak

    (Genome Biology Unit, European Molecular Biology Laboratory (EMBL))

  • Serap Erkek

    (German Cancer Research Center (DKFZ)
    Genome Biology Unit, European Molecular Biology Laboratory (EMBL))

  • David T. W. Jones

    (German Cancer Research Center (DKFZ)
    German Cancer Consortium (DKTK))

  • Barbara C. Worst

    (German Cancer Research Center (DKFZ)
    German Cancer Consortium (DKTK))

  • Marcel Kool

    (German Cancer Research Center (DKFZ)
    German Cancer Consortium (DKTK))

  • Marc Zapatka

    (German Cancer Research Center (DKFZ))

  • Natalie Jäger

    (German Cancer Research Center (DKFZ))

  • Lukas Chavez

    (German Cancer Research Center (DKFZ)
    German Cancer Consortium (DKTK))

  • Barbara Hutter

    (German Cancer Research Center (DKFZ))

  • Matthias Bieg

    (German Cancer Research Center (DKFZ)
    Heidelberg Center for Personalized Oncology (DKFZ-HIPO), German Cancer Research Center (DKFZ))

  • Nagarajan Paramasivam

    (German Cancer Research Center (DKFZ)
    Medical Faculty Heidelberg, Heidelberg University)

  • Michael Heinold

    (German Cancer Research Center (DKFZ)
    Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University)

  • Zuguang Gu

    (German Cancer Research Center (DKFZ)
    Heidelberg Center for Personalized Oncology (DKFZ-HIPO), German Cancer Research Center (DKFZ))

  • Naveed Ishaque

    (German Cancer Research Center (DKFZ)
    Heidelberg Center for Personalized Oncology (DKFZ-HIPO), German Cancer Research Center (DKFZ))

  • Christina Jäger-Schmidt

    (German Cancer Research Center (DKFZ))

  • Charles D. Imbusch

    (German Cancer Research Center (DKFZ))

  • Alke Jugold

    (German Cancer Research Center (DKFZ))

  • Daniel Hübschmann

    (German Cancer Research Center (DKFZ)
    Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University
    Heidelberg University Hospital)

  • Thomas Risch

    (Max Planck Institute for Molecular Genetics)

  • Vyacheslav Amstislavskiy

    (Max Planck Institute for Molecular Genetics)

  • Francisco German Rodriguez Gonzalez

    (Biotech Research & Innovation Centre (BRIC), Copenhagen University and Finsen Laboratory)

  • Ursula D. Weber

    (German Cancer Research Center (DKFZ))

  • Stephan Wolf

    (Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ))

  • Giles W. Robinson

    (St Jude Children’s Research Hospital)

  • Xin Zhou

    (St Jude Children’s Research Hospital)

  • Gang Wu

    (St Jude Children’s Research Hospital)

  • David Finkelstein

    (St Jude Children’s Research Hospital)

  • Yanling Liu

    (St Jude Children’s Research Hospital)

  • Florence M. G. Cavalli

    (Developmental & Stem Cell Biology Program, The Hospital for Sick Children)

  • Betty Luu

    (Developmental & Stem Cell Biology Program, The Hospital for Sick Children)

  • Vijay Ramaswamy

    (Developmental & Stem Cell Biology Program, The Hospital for Sick Children)

  • Xiaochong Wu

    (Developmental & Stem Cell Biology Program, The Hospital for Sick Children)

  • Jan Koster

    (Amsterdam Medical Center)

  • Marina Ryzhova

    (NN Burdenko Neurosurgical Institute)

  • Yoon-Jae Cho

    (Papé Family Pediatric Research Institute, Knight Cancer Institute, Oregon Health and Science University)

  • Scott L. Pomeroy

    (Boston Children's Hospital and Harvard Medical School)

  • Christel Herold-Mende

    (University Clinic, Heidelberg University, Heidelberg Hospital)

  • Martin Schuhmann

    (University Hospital Tübingen)

  • Martin Ebinger

    (Children’s University Hospital Tübingen)

  • Linda M. Liau

    (David Geffen School of Medicine at UCLA)

  • Jaume Mora

    (Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu)

  • Roger E. McLendon

    (Duke University)

  • Nada Jabado

    (McGill University)

  • Toshihiro Kumabe

    (Kitasato University School of Medicine)

  • Eric Chuah

    (Michael Smith Genome Sciences Centre, BC Cancer Agency)

  • Yussanne Ma

    (Michael Smith Genome Sciences Centre, BC Cancer Agency)

  • Richard A. Moore

    (Michael Smith Genome Sciences Centre, BC Cancer Agency)

  • Andrew J. Mungall

    (Michael Smith Genome Sciences Centre, BC Cancer Agency)

  • Karen L. Mungall

    (Michael Smith Genome Sciences Centre, BC Cancer Agency)

  • Nina Thiessen

    (Michael Smith Genome Sciences Centre, BC Cancer Agency)

  • Kane Tse

    (Michael Smith Genome Sciences Centre, BC Cancer Agency)

  • Tina Wong

    (Michael Smith Genome Sciences Centre, BC Cancer Agency)

  • Steven J. M. Jones

    (Michael Smith Genome Sciences Centre, BC Cancer Agency)

  • Olaf Witt

    (Heidelberg University Hospital)

  • Till Milde

    (Heidelberg University Hospital)

  • Andreas Von Deimling

    (Heidelberg University Hospital)

  • David Capper

    (Heidelberg University Hospital)

  • Andrey Korshunov

    (Heidelberg University Hospital)

  • Marie-Laure Yaspo

    (Max Planck Institute for Molecular Genetics)

  • Richard Kriwacki

    (St Jude Children’s Research Hospital)

  • Amar Gajjar

    (St Jude Children’s Research Hospital)

  • Jinghui Zhang

    (St Jude Children’s Research Hospital)

  • Rameen Beroukhim

    (Broad Institute of Harvard and MIT)

  • Ernest Fraenkel

    (Massachusetts Institute of Technology)

  • Jan O. Korbel

    (Genome Biology Unit, European Molecular Biology Laboratory (EMBL))

  • Benedikt Brors

    (German Cancer Research Center (DKFZ)
    German Cancer Research Center (DKFZ)
    German Cancer Consortium (DKTK))

  • Matthias Schlesner

    (German Cancer Research Center (DKFZ))

  • Roland Eils

    (German Cancer Research Center (DKFZ)
    Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University
    German Cancer Consortium (DKTK))

  • Marco A. Marra

    (Michael Smith Genome Sciences Centre, BC Cancer Agency)

  • Stefan M. Pfister

    (German Cancer Research Center (DKFZ)
    German Cancer Consortium (DKTK)
    Heidelberg University Hospital)

  • Michael D. Taylor

    (Developmental & Stem Cell Biology Program, The Hospital for Sick Children
    Hospital for Sick Children)

  • Peter Lichter

    (German Cancer Research Center (DKFZ)
    German Cancer Consortium (DKTK))

Abstract

Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and ‘enhancer hijacking’ events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma.

Suggested Citation

  • Paul A. Northcott & Ivo Buchhalter & A. Sorana Morrissy & Volker Hovestadt & Joachim Weischenfeldt & Tobias Ehrenberger & Susanne Gröbner & Maia Segura-Wang & Thomas Zichner & Vasilisa A. Rudneva & Ha, 2017. "The whole-genome landscape of medulloblastoma subtypes," Nature, Nature, vol. 547(7663), pages 311-317, July.
  • Handle: RePEc:nat:nature:v:547:y:2017:i:7663:d:10.1038_nature22973
    DOI: 10.1038/nature22973
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    Cited by:

    1. 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.
    2. Fengju Chen & Yiqun Zhang & Lanlan Shen & Chad J. Creighton, 2024. "The DNA methylome of pediatric brain tumors appears shaped by structural variation and predicts survival," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Min Kyung Lee & Nasim Azizgolshani & Ze Zhang & Laurent Perreard & Fred W. Kolling & Lananh N. Nguyen & George J. Zanazzi & Lucas A. Salas & Brock C. Christensen, 2024. "Associations in cell type-specific hydroxymethylation and transcriptional alterations of pediatric central nervous system tumors," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    4. Yafei Jiang & Jinzeng Wang & Mengxiong Sun & Dongqing Zuo & Hongsheng Wang & Jiakang Shen & Wenyan Jiang & Haoran Mu & Xiaojun Ma & Fei Yin & Jun Lin & Chongren Wang & Shuting Yu & Lu Jiang & Gang Lv , 2022. "Multi-omics analysis identifies osteosarcoma subtypes with distinct prognosis indicating stratified treatment," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. Oliver J. Mainwaring & Holger Weishaupt & Miao Zhao & Gabriela Rosén & Anna Borgenvik & Laura Breinschmid & Annemieke D. Verbaan & Stacey Richardson & Dean Thompson & Steven C. Clifford & Rebecca M. H, 2023. "ARF suppression by MYC but not MYCN confers increased malignancy of aggressive pediatric brain tumors," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    6. Min Kyung Lee & Nasim Azizgolshani & Joshua A. Shapiro & Lananh N. Nguyen & Fred W. Kolling & George J. Zanazzi & Hildreth Robert Frost & Brock C. Christensen, 2024. "Identifying tumor type and cell type-specific gene expression alterations in pediatric central nervous system tumors," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    7. 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.
    8. Melanie Schoof & Shweta Godbole & Thomas K. Albert & Matthias Dottermusch & Carolin Walter & Annika Ballast & Nan Qin & Marlena Baca Olivera & Carolin Göbel & Sina Neyazi & Dörthe Holdhof & Catena Kre, 2023. "Mouse models of pediatric high-grade gliomas with MYCN amplification reveal intratumoral heterogeneity and lineage signatures," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    9. 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.
    10. Noha A. M. Shendy & Melissa Bikowitz & Logan H. Sigua & Yang Zhang & Audrey Mercier & Yousef Khashana & Stephanie Nance & Qi Liu & Ian M. Delahunty & Sarah Robinson & Vanshita Goel & Matthew G. Rees &, 2024. "Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    11. 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.
    12. David R. Ghasemi & Konstantin Okonechnikov & Anne Rademacher & Stephan Tirier & Kendra K. Maass & Hanna Schumacher & Piyush Joshi & Maxwell P. Gold & Julia Sundheimer & Britta Statz & Ahmet S. Rifaiog, 2024. "Compartments in medulloblastoma with extensive nodularity are connected through differentiation along the granular precursor lineage," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    13. Silvia Pomella & Matteo Cassandri & Lucrezia D’Archivio & Antonella Porrazzo & Cristina Cossetti & Doris Phelps & Clara Perrone & Michele Pezzella & Antonella Cardinale & Marco Wachtel & Sara Aloisi &, 2023. "MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    14. Shweta Godbole & Hannah Voß & Antonia Gocke & Simon Schlumbohm & Yannis Schumann & Bojia Peng & Martin Mynarek & Stefan Rutkowski & Matthias Dottermusch & Mario M. Dorostkar & Andrey Korshunov & Thoma, 2024. "Multiomic profiling of medulloblastoma reveals subtype-specific targetable alterations at the proteome and N-glycan level," Nature Communications, Nature, vol. 15(1), pages 1-24, December.

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