The transcriptional landscape of Shh medulloblastoma

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 Zheng, Shizhong Dai, Ana S. Guerreiro Stucklin, Maria C. Vladoiu, Vernon Fong, Borja L. Holgado, Carolina Nor, Xiaochong Wu, Diala Abd-Rabbo, Pierre Bérubé, Yu Chang Wang, Betty Luu, Raul A. Suarez, Avesta Rastan, Aaron H. Gillmor, John J. Y. Lee, Xiao Yun Zhang, Craig Daniels, Peter Dirks, David Malkin, Eric Bouffet, Uri Tabori, James Loukides, François P. Doz, Franck Bourdeaut, Olivier O. Delattre, Julien Masliah-Planchon, Olivier Ayrault, Seung-Ki Kim, David Meyronet, Wieslawa A. Grajkowska, Carlos G. Carlotti, Carmen Torres, Jaume Mora, Charles G. Eberhart, Erwin G. Meir, Toshihiro Kumabe, Pim J. French, Johan M. Kros, Nada Jabado, Boleslaw Lach, Ian F. Pollack, Ronald L. Hamilton, Amulya A. Nageswara Rao, Caterina Giannini, James M. Olson, László Bognár, Almos Klekner, Karel Zitterbart, Joanna J. Phillips, Reid C. Thompson, Michael K. Cooper, Joshua B. Rubin, Linda M. Liau, Miklós Garami, Peter Hauser, Kay Ka Wai Li, Ho-Keung Ng, Wai Sang Poon, G. Yancey Gillespie, Jennifer A. Chan, Shin Jung, Roger E. McLendon, Eric M. Thompson, David Zagzag, Rajeev Vibhakar, Young Shin Ra, Maria Luisa Garre, Ulrich Schüller, Tomoko Shofuda, Claudia C. Faria, Enrique López-Aguilar, Gelareh Zadeh, Chi-Chung Hui, Vijay Ramaswamy, Swneke D. Bailey, Steven J. Jones, Andrew J. Mungall, Richard A. Moore, John A. Calarco, Lincoln D. Stein, Gary D. Bader, Jüri Reimand, Jiannis Ragoussis, William A. Weiss, Marco A. Marra, Hiromichi Suzuki () and Michael D. Taylor ()
Additional contact information
Patryk Skowron: The Hospital for Sick Children
Hamza Farooq: The Hospital for Sick Children
Florence M. G. Cavalli: The Hospital for Sick Children
A. Sorana Morrissy: University of Calgary
Michelle Ly: The Hospital for Sick Children
Liam D. Hendrikse: The Hospital for Sick Children
Evan Y. Wang: The Hospital for Sick Children
Haig Djambazian: McGill University
Helen Zhu: University of Toronto
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
Maria C. Vladoiu: The Hospital for Sick Children
Vernon Fong: The Hospital for Sick Children
Borja L. Holgado: The Hospital for Sick Children
Carolina Nor: The Hospital for Sick Children
Xiaochong Wu: 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
Raul A. Suarez: The Hospital for Sick Children
Avesta Rastan: The Hospital for Sick Children
Aaron H. Gillmor: University of Calgary
John J. Y. Lee: The Hospital for Sick Children
Xiao Yun Zhang: The Hospital for Sick Children
Craig Daniels: The Hospital for Sick Children
Peter Dirks: The Hospital for Sick Children
David Malkin: University of Toronto
Eric Bouffet: The Hospital for Sick Children
Uri Tabori: 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
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
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
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
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
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
Chi-Chung Hui: The Hospital for Sick Children
Vijay Ramaswamy: The Hospital for Sick Children
Swneke D. Bailey: McGill University
Steven J. Jones: Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency
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
Gary D. Bader: University of Toronto
Jüri Reimand: University of Toronto
Jiannis Ragoussis: McGill University
William A. Weiss: University of California San Francisco
Marco A. Marra: Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency
Hiromichi Suzuki: The Hospital for Sick Children
Michael D. Taylor: The Hospital for Sick Children

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21883-0

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