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The transcriptional landscape of Shh medulloblastoma

Author

Listed:
  • Patryk Skowron

    (The Hospital for Sick Children
    University of Toronto
    The Hospital for Sick Children)

  • Hamza Farooq

    (The Hospital for Sick Children
    University of Toronto
    The Hospital for Sick Children)

  • Florence M. G. Cavalli

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • A. Sorana Morrissy

    (University of Calgary
    Alberta Children’s Hospital Research Institute
    University of Calgary)

  • Michelle Ly

    (The Hospital for Sick Children
    University of Toronto
    The Hospital for Sick Children)

  • Liam D. Hendrikse

    (The Hospital for Sick Children
    The Hospital for Sick Children
    University of Toronto)

  • Evan Y. Wang

    (The Hospital for Sick Children
    The Hospital for Sick Children
    University of Toronto)

  • Haig Djambazian

    (McGill University
    McGill University)

  • Helen Zhu

    (University of Toronto
    Computational Biology Program, Ontario Institute for Cancer Research)

  • Karen L. Mungall

    (Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency)

  • Quang M. Trinh

    (Computational Biology Program, Ontario Institute for Cancer Research)

  • Tina Zheng

    (University of California San Francisco)

  • Shizhong Dai

    (University of California San Francisco)

  • Ana S. Guerreiro Stucklin

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Maria C. Vladoiu

    (The Hospital for Sick Children
    University of Toronto
    The Hospital for Sick Children)

  • Vernon Fong

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Borja L. Holgado

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Carolina Nor

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Xiaochong Wu

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Diala Abd-Rabbo

    (Computational Biology Program, Ontario Institute for Cancer Research)

  • Pierre Bérubé

    (McGill University)

  • Yu Chang Wang

    (McGill University)

  • Betty Luu

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Raul A. Suarez

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Avesta Rastan

    (The Hospital for Sick Children
    The Hospital for Sick Children
    University of Toronto)

  • Aaron H. Gillmor

    (University of Calgary
    Alberta Children’s Hospital Research Institute
    University of Calgary)

  • John J. Y. Lee

    (The Hospital for Sick Children
    University of Toronto
    The Hospital for Sick Children)

  • Xiao Yun Zhang

    (The Hospital for Sick Children)

  • Craig Daniels

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Peter Dirks

    (The Hospital for Sick Children
    The Hospital for Sick Children
    Division of Neurosurgery, The Hospital for Sick Children
    University of Toronto)

  • David Malkin

    (University of Toronto
    Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children)

  • Eric Bouffet

    (The Hospital for Sick Children
    Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children)

  • Uri Tabori

    (The Hospital for Sick Children
    University of Toronto
    Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children)

  • James Loukides

    (The Hospital for Sick Children)

  • François P. Doz

    (University of Paris)

  • Franck Bourdeaut

    (University of Paris)

  • Olivier O. Delattre

    (INSERM U 830, Institut Curie)

  • Julien Masliah-Planchon

    (Unit of Somatic Genetics, Institut Curie)

  • Olivier Ayrault

    (PSL Research University, Université Paris Sud, Université Paris-Saclay, CNRS UMR 3347, INSERM U1021, Institut Curie)

  • Seung-Ki Kim

    (Seoul National University Children’s Hospital)

  • David Meyronet

    (Hospices Civils de Lyon, Institute of Pathology, University Lyon 1, Department of Cancer Cell Plasticity–INSERM U1052 Cancer Research Center of Lyon)

  • Wieslawa A. Grajkowska

    (Department of Pathology, The Children’s Memorial Health Institute)

  • Carlos G. Carlotti

    (University of Sao Paulo)

  • Carmen Torres

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

  • Jaume Mora

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

  • Charles G. Eberhart

    (John Hopkins University School of Medicine)

  • Erwin G. Meir

    (Emory University)

  • Toshihiro Kumabe

    (Kitasato University School of Medicine)

  • Pim J. French

    (Erasmus University Medical Center)

  • Johan M. Kros

    (Department of Pathology, Erasmus University Medical Center)

  • Nada Jabado

    (McGill University)

  • Boleslaw Lach

    (Department of Pathology and Molecular Medicine, Division of Anatomical Pathology, McMaster University
    Department of Pathology and Laboratory Medicine, Hamilton General Hospital)

  • Ian F. Pollack

    (Department of Neurological Surgery, University of Pittsburgh School of Medicine)

  • Ronald L. Hamilton

    (Department of Pathology, University of Pittsburgh School of Medicine)

  • Amulya A. Nageswara Rao

    (Division of Pediatric Hematology/Oncology, Mayo Clinic)

  • Caterina Giannini

    (Department of Laboratory Medicine and Pathology, Mayo Clinic)

  • James M. Olson

    (Clinical Research Division, Fred Hutchinson Cancer Research Center)

  • László Bognár

    (Department of Neurosurgery, University of Debrecen, Medical and Health Science Centre)

  • Almos Klekner

    (Department of Neurosurgery, University of Debrecen, Medical and Health Science Centre)

  • Karel Zitterbart

    (Department of Pediatric Oncology, Masaryk University School of Medicine)

  • Joanna J. Phillips

    (Department of Neurological Surgery, University of California San Francisco
    Department of Pathology, University of California San Francisco)

  • Reid C. Thompson

    (Department of Neurological Surgery, Vanderbilt Medical Center)

  • Michael K. Cooper

    (Department of Neurology, Vanderbilt Medical Center)

  • Joshua B. Rubin

    (Departments of Neuroscience, Washington University School of Medicine in St. Louis)

  • Linda M. Liau

    (Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles)

  • Miklós Garami

    (Semmelweis University)

  • Peter Hauser

    (Semmelweis University)

  • Kay Ka Wai Li

    (The Chinese University of Hong Kong)

  • Ho-Keung Ng

    (The Chinese University of Hong Kong)

  • Wai Sang Poon

    (The Chinese University of Hong Kong)

  • G. Yancey Gillespie

    (Department of Neurosurgery, University of Alabama at Birmingham)

  • Jennifer A. Chan

    (University of Calgary)

  • Shin Jung

    (Department of Neurosurgery, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Hwasun Hospital and Medical School)

  • Roger E. McLendon

    (Duke University
    Department of Neurosurgery, Duke University)

  • Eric M. Thompson

    (Department of Neurosurgery, Duke University)

  • David Zagzag

    (Department of Pathology and Neurosurgery, NYU Grossman School of Medicine and NYU Langone Health)

  • Rajeev Vibhakar

    (Department of Pediatrics, University of Colorado Denver)

  • Young Shin Ra

    (University of Ulsan, Asan Medical Center)

  • Maria Luisa Garre

    (U.O. Neurochirurgia, Istituto Giannina Gaslini)

  • Ulrich Schüller

    (Institute of Neuropathology, University Medical Center
    Research Institute Children’s Cancer Center
    Pediatric Hematology and Oncology, University Medical Center)

  • Tomoko Shofuda

    (Division of Stem Cell Research, Institute for Clinical Research, Osaka National Hospital)

  • Claudia C. Faria

    (Division of Neurosurgery, Centro Hospitalar Lisboa Norte (CHULN), Hospital de Santa Maria
    Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa)

  • Enrique López-Aguilar

    (Division of Pediatric Hematology/Oncology, Hospital Pediatría Centro Médico Nacional century XXI)

  • Gelareh Zadeh

    (Division of Neurosurgery, Toronto Western Hospital, University Health Network
    University Health Network)

  • Chi-Chung Hui

    (The Hospital for Sick Children
    University of Toronto)

  • Vijay Ramaswamy

    (The Hospital for Sick Children
    The Hospital for Sick Children
    University of Toronto
    Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children)

  • Swneke D. Bailey

    (McGill University
    Cancer Research Program, Research Institute of the McGill University Health Centre)

  • Steven J. Jones

    (Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency
    Department of Medical Genetics, University of British Columbia
    Simon Fraser University)

  • Andrew J. Mungall

    (Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency)

  • Richard A. Moore

    (Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency)

  • John A. Calarco

    (Department of Cell & Systems Biology, University of Toronto)

  • Lincoln D. Stein

    (University of Toronto
    Adaptive Oncology, Ontario Institute for Cancer Research)

  • Gary D. Bader

    (University of Toronto
    The Donnelly Centre, University of Toronto)

  • Jüri Reimand

    (University of Toronto
    Computational Biology Program, Ontario Institute for Cancer Research
    University of Toronto)

  • Jiannis Ragoussis

    (McGill University
    McGill University)

  • William A. Weiss

    (University of California San Francisco
    Department of Neurological Surgery, University of California San Francisco
    Department of Pediatrics, University of California San Francisco)

  • Marco A. Marra

    (Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency
    Department of Medical Genetics, University of British Columbia)

  • Hiromichi Suzuki

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Michael D. Taylor

    (The Hospital for Sick Children
    University of Toronto
    The Hospital for Sick Children
    University of Toronto)

Abstract

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.

Suggested Citation

  • Patryk Skowron & Hamza Farooq & Florence M. G. Cavalli & A. Sorana Morrissy & Michelle Ly & Liam D. Hendrikse & Evan Y. Wang & Haig Djambazian & Helen Zhu & Karen L. Mungall & Quang M. Trinh & Tina Zh, 2021. "The transcriptional landscape of Shh medulloblastoma," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21883-0
    DOI: 10.1038/s41467-021-21883-0
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    Cited by:

    1. Ling-Hui Zeng & Chao Tang & Minli Yao & Qiangqiang He & Meiyu Qv & Qianlei Ren & Yana Xu & Tingyu Shen & Weizhong Gu & Chengyun Xu & Chaochun Zou & Xing Ji & Ximei Wu & Jirong Wang, 2024. "Phosphorylation of human glioma-associated oncogene 1 on Ser937 regulates Sonic Hedgehog signaling in medulloblastoma," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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