. 2017 Jun 12;31(6):737-754.e6.

doi: 10.1016/j.ccell.2017.05.005.

Intertumoral Heterogeneity within Medulloblastoma Subgroups

Florence M G Cavalli¹, Marc Remke², Ladislav Rampasek³, John Peacock⁴, David J H Shih⁴, Betty Luu¹, Livia Garzia¹, Jonathon Torchia⁵, Carolina Nor¹, A Sorana Morrissy¹, Sameer Agnihotri⁶, Yuan Yao Thompson⁴, Claudia M Kuzan-Fischer¹, Hamza Farooq⁴, Keren Isaev⁷, Craig Daniels¹, Byung-Kyu Cho⁸, Seung-Ki Kim⁸, Kyu-Chang Wang⁸, Ji Yeoun Lee⁸, Wieslawa A Grajkowska⁹, Marta Perek-Polnik¹⁰, Alexandre Vasiljevic¹¹, Cecile Faure-Conter¹², Anne Jouvet¹³, Caterina Giannini¹⁴, Amulya A Nageswara Rao¹⁵, Kay Ka Wai Li¹⁶, Ho-Keung Ng¹⁶, Charles G Eberhart¹⁷, Ian F Pollack¹⁸, Ronald L Hamilton¹⁹, G Yancey Gillespie²⁰, James M Olson²¹, Sarah Leary²², William A Weiss²³, Boleslaw Lach²⁴, Lola B Chambless²⁵, Reid C Thompson²⁵, Michael K Cooper²⁶, Rajeev Vibhakar²⁷, Peter Hauser²⁸, Marie-Lise C van Veelen²⁹, Johan M Kros³⁰, Pim J French³¹, Young Shin Ra³², Toshihiro Kumabe³³, Enrique López-Aguilar³⁴, Karel Zitterbart³⁵, Jaroslav Sterba³⁵, Gaetano Finocchiaro³⁶, Maura Massimino³⁷, Erwin G Van Meir³⁸, Satoru Osuka³⁸, Tomoko Shofuda³⁹, Almos Klekner⁴⁰, Massimo Zollo⁴¹, Jeffrey R Leonard⁴², Joshua B Rubin⁴³, Nada Jabado⁴⁴, Steffen Albrecht⁴⁵, Jaume Mora⁴⁶, Timothy E Van Meter⁴⁷, Shin Jung⁴⁸, Andrew S Moore⁴⁹, Andrew R Hallahan⁴⁹, Jennifer A Chan⁵⁰, Daniela P C Tirapelli⁵¹, Carlos G Carlotti⁵¹, Maryam Fouladi⁵², José Pimentel⁵³, Claudia C Faria⁵⁴, Ali G Saad⁵⁵, Luca Massimi⁵⁶, Linda M Liau⁵⁷, Helen Wheeler⁵⁸, Hideo Nakamura⁵⁹, Samer K Elbabaa⁶⁰, Mario Perezpeña-Diazconti⁶¹, Fernando Chico Ponce de León⁶², Shenandoah Robinson⁶³, Michal Zapotocky⁶⁴, Alvaro Lassaletta⁶⁴, Annie Huang⁶⁵, Cynthia E Hawkins⁶⁶, Uri Tabori⁶⁵, Eric Bouffet⁶⁵, Ute Bartels⁶⁴, Peter B Dirks⁶⁷, James T Rutka⁶⁸, Gary D Bader⁶⁹, Jüri Reimand⁷, Anna Goldenberg⁷⁰, Vijay Ramaswamy⁷¹, Michael D Taylor⁷²

Affiliations

¹ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
² Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf 40225, Germany; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A1, Canada; Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Düsseldorf 40225, Germany.
³ Department of Computer Science, University of Toronto, Toronto, ON M5S 2E4, Canada; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁴ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A1, Canada.
⁵ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A1, Canada.
⁶ UPCI Brain Tumor Program, University of Pittsburgh, Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.
⁷ Informatics Program, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
⁸ Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul 30322, South Korea.
⁹ Department of Pathology, The Children's Memorial Health Institute, University of Warsaw, Warsaw 04-730, Poland.
¹⁰ Department of Oncology, The Children's Memorial Health Institute, University of Warsaw, Warsaw 04-730, Poland.
¹¹ Centre de Pathologie et Neuropathologie Est, Centre de Biologie et Pathologie Est, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron 69677, France; ONCOFLAM - Neuro-Oncologie et Neuro-Inflammation Centre de Recherche en Neurosciences de Lyon, Lyon 69008, France.
¹² Institute of Pediatric Hematology and Oncology, Lyon 69008, France.
¹³ Centre de Pathologie EST, Groupement Hospitalier EST, Université de Lyon, Bron 69677, France.
¹⁴ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
¹⁵ Division of Pediatric Hematology/Oncology, Mayo Clinic, Rochester, MN 55905, USA.
¹⁶ Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.
¹⁷ Departments of Pathology, Ophthalmology and Oncology, John Hopkins University School of Medicine, Baltimore, MD 21287, USA.
¹⁸ Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
¹⁹ Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
²⁰ Department of Surgery, Division of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
²¹ Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA; Division of Pediatric Hematology/Oncology, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, WA 98145-5005, USA.
²² Division of Pediatric Hematology/Oncology, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, WA 98145-5005, USA.
²³ Departments of Pediatrics, Neurological Surgery and Neurology, University of California San Francisco, San Francisco, CA 94143-0112, USA.
²⁴ Division of Anatomical Pathology, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada; Department of Pathology and Laboratory Medicine, Hamilton General Hospital, Hamilton, ON L8L 2X2, Canada.
²⁵ Department of Neurological Surgery, Vanderbilt Medical Center, Nashville, TN 37232, USA.
²⁶ Department of Neurology, Vanderbilt Medical Center, Nashville, TN 37232, USA.
²⁷ Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045, USA.
²⁸ 2nd Department of Pediatrics, Semmelweis University, Budapest 1094, Hungary.
²⁹ Department of Neurosurgery, Erasmus University Medical Center, Rotterdam 3015 CE, the Netherlands.
³⁰ Department of Pathology, Erasmus University Medical Center, Rotterdam 3015 CN, the Netherlands.
³¹ Department of Neurology, Erasmus University Medical Center, Rotterdam 3015 CE, the Netherlands.
³² Department of Neurosurgery, University of Ulsan, Asan Medical Center, Seoul 05505, South Korea.
³³ Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.
³⁴ Division of Pediatric Hematology/Oncology, Hospital Pediatría Centro Médico Nacional Century XXI, Mexico City 06720, Mexico.
³⁵ Department of Pediatric Oncology, School of Medicine, Masaryk University, Brno 625 00, Czech Republic.
³⁶ Department of Neuro-Oncology, Istituto Neurologico Besta, Milan 20133, Italy.
³⁷ Fondazione IRCCS Istituto Nazionale Tumori, Milan 20133, Italy.
³⁸ Department of Hematology & Medical Oncology, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
³⁹ Division of Stem Cell Research, Institute for Clinical Research, Osaka National Hospital, Osaka 540-0006, Japan.
⁴⁰ Department of Neurosurgery, University of Debrecen, Medical and Health Science Centre, Debrecen 4032, Hungary.
⁴¹ Dipartimento di Biochimica e Biotecnologie Mediche, University of Naples, Naples 80145, Italy.
⁴² Division of Pediatric Neurosurgery, Department of Neurosurgery, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, MO 63110, USA.
⁴³ Departments of Pediatrics, Anatomy and Neurobiology, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, MO 63110, USA.
⁴⁴ Division of Hematology/Oncology, Department of Pediatrics, McGill University, Montreal, QC H4A 3J1, Canada.
⁴⁵ Department of Pathology, McGill University, Montreal, QC H4A 3J1, Canada; Department of Pathology, Montreal Children's Hospital, Montreal, QC H4A 3J1, Canada.
⁴⁶ Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona 08950, Spain.
⁴⁷ Department of Pediatrics, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298-0646, USA.
⁴⁸ Department of Neurosurgery, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Hwasun Hospital and Medical School, Hwasun-gun 519-763, Chonnam South Korea.
⁴⁹ Lady Cilento Children's Hospital, The University of Queensland, Brisbane QLD 4102, Australia; Oncology Service, Children's Health Queensland Hospital and Health Service, South Brisbane, QLD 4029, Australia.
⁵⁰ Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB T2N 2T9, Canada.
⁵¹ Department of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, University of São Paulo, São Paulo 14049-900, Brazil.
⁵² Division of Hematology/Oncology, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
⁵³ Divison of Pathology, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon 1649-035, Portugal.
⁵⁴ Division of Neurosurgery, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon 1649-035, Portugal.
⁵⁵ Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
⁵⁶ Department of Pediatric Neurosurgery, Catholic University Medical School, Rome 00198, Italy.
⁵⁷ Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
⁵⁸ Kolling Institute of Medical Research, The University of Sydney, Sydney, NSW 2065, Australia.
⁵⁹ Department of Neurosurgery, Kumamoto University Graduate School of Medical Science, Kumamoto 860-8555, Japan.
⁶⁰ Division of Pediatric Neurosurgery, Department of Neurosurgery, Saint Louis University School of Medicine, St. Louis, MO, USA.
⁶¹ Department of Pathology, Hospital Infantil de Mexico Federico Gomez, Mexico City 06720, Mexico.
⁶² Department of Neurosurgery, Hospital Infantil de Mexico Federico Gomez, Mexico City 06720, Mexico.
⁶³ Division of Pediatric Neurosurgery, Rainbow & Babies Children's Hospital, Case Western Reserve, Cleveland, OH 44106, USA.
⁶⁴ Division of Haematology / Oncology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁶⁵ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Division of Haematology / Oncology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁶⁶ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Division of Pathology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁶⁷ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁶⁸ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A1, Canada; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁶⁹ The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Banting and Best Department of Medical Research, University of Toronto, Toronto, ON M5G 1L6, Canada; McLaughlin Centre, University of Toronto, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Samuel Lunenfeld Research Institute at Mount Sinai Hospital, University of Toronto, Toronto, ON M5G 1X5, Canada.
⁷⁰ Department of Computer Science, University of Toronto, Toronto, ON M5S 2E4, Canada; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada. Electronic address: anna.goldenberg@utoronto.ca.
⁷¹ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Division of Haematology / Oncology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Program in Neuroscience and Mental Health and Division of Neurology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada. Electronic address: vijay.ramaswamy@sickkids.ca.
⁷² The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A1, Canada; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada. Electronic address: mdtaylor@sickkids.ca.

PMID: 28609654
PMCID: PMC6163053
DOI: 10.1016/j.ccell.2017.05.005

Intertumoral Heterogeneity within Medulloblastoma Subgroups

Florence M G Cavalli et al. Cancer Cell. 2017.

. 2017 Jun 12;31(6):737-754.e6.

doi: 10.1016/j.ccell.2017.05.005.

Authors

Affiliations

¹ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
² Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf 40225, Germany; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A1, Canada; Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Düsseldorf 40225, Germany.
³ Department of Computer Science, University of Toronto, Toronto, ON M5S 2E4, Canada; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁴ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A1, Canada.
⁵ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A1, Canada.
⁶ UPCI Brain Tumor Program, University of Pittsburgh, Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.
⁷ Informatics Program, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
⁸ Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul 30322, South Korea.
⁹ Department of Pathology, The Children's Memorial Health Institute, University of Warsaw, Warsaw 04-730, Poland.
¹⁰ Department of Oncology, The Children's Memorial Health Institute, University of Warsaw, Warsaw 04-730, Poland.
¹¹ Centre de Pathologie et Neuropathologie Est, Centre de Biologie et Pathologie Est, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron 69677, France; ONCOFLAM - Neuro-Oncologie et Neuro-Inflammation Centre de Recherche en Neurosciences de Lyon, Lyon 69008, France.
¹² Institute of Pediatric Hematology and Oncology, Lyon 69008, France.
¹³ Centre de Pathologie EST, Groupement Hospitalier EST, Université de Lyon, Bron 69677, France.
¹⁴ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
¹⁵ Division of Pediatric Hematology/Oncology, Mayo Clinic, Rochester, MN 55905, USA.
¹⁶ Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.
¹⁷ Departments of Pathology, Ophthalmology and Oncology, John Hopkins University School of Medicine, Baltimore, MD 21287, USA.
¹⁸ Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
¹⁹ Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
²⁰ Department of Surgery, Division of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
²¹ Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA; Division of Pediatric Hematology/Oncology, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, WA 98145-5005, USA.
²² Division of Pediatric Hematology/Oncology, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, WA 98145-5005, USA.
²³ Departments of Pediatrics, Neurological Surgery and Neurology, University of California San Francisco, San Francisco, CA 94143-0112, USA.
²⁴ Division of Anatomical Pathology, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada; Department of Pathology and Laboratory Medicine, Hamilton General Hospital, Hamilton, ON L8L 2X2, Canada.
²⁵ Department of Neurological Surgery, Vanderbilt Medical Center, Nashville, TN 37232, USA.
²⁶ Department of Neurology, Vanderbilt Medical Center, Nashville, TN 37232, USA.
²⁷ Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045, USA.
²⁸ 2nd Department of Pediatrics, Semmelweis University, Budapest 1094, Hungary.
²⁹ Department of Neurosurgery, Erasmus University Medical Center, Rotterdam 3015 CE, the Netherlands.
³⁰ Department of Pathology, Erasmus University Medical Center, Rotterdam 3015 CN, the Netherlands.
³¹ Department of Neurology, Erasmus University Medical Center, Rotterdam 3015 CE, the Netherlands.
³² Department of Neurosurgery, University of Ulsan, Asan Medical Center, Seoul 05505, South Korea.
³³ Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.
³⁴ Division of Pediatric Hematology/Oncology, Hospital Pediatría Centro Médico Nacional Century XXI, Mexico City 06720, Mexico.
³⁵ Department of Pediatric Oncology, School of Medicine, Masaryk University, Brno 625 00, Czech Republic.
³⁶ Department of Neuro-Oncology, Istituto Neurologico Besta, Milan 20133, Italy.
³⁷ Fondazione IRCCS Istituto Nazionale Tumori, Milan 20133, Italy.
³⁸ Department of Hematology & Medical Oncology, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
³⁹ Division of Stem Cell Research, Institute for Clinical Research, Osaka National Hospital, Osaka 540-0006, Japan.
⁴⁰ Department of Neurosurgery, University of Debrecen, Medical and Health Science Centre, Debrecen 4032, Hungary.
⁴¹ Dipartimento di Biochimica e Biotecnologie Mediche, University of Naples, Naples 80145, Italy.
⁴² Division of Pediatric Neurosurgery, Department of Neurosurgery, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, MO 63110, USA.
⁴³ Departments of Pediatrics, Anatomy and Neurobiology, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, MO 63110, USA.
⁴⁴ Division of Hematology/Oncology, Department of Pediatrics, McGill University, Montreal, QC H4A 3J1, Canada.
⁴⁵ Department of Pathology, McGill University, Montreal, QC H4A 3J1, Canada; Department of Pathology, Montreal Children's Hospital, Montreal, QC H4A 3J1, Canada.
⁴⁶ Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona 08950, Spain.
⁴⁷ Department of Pediatrics, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298-0646, USA.
⁴⁸ Department of Neurosurgery, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Hwasun Hospital and Medical School, Hwasun-gun 519-763, Chonnam South Korea.
⁴⁹ Lady Cilento Children's Hospital, The University of Queensland, Brisbane QLD 4102, Australia; Oncology Service, Children's Health Queensland Hospital and Health Service, South Brisbane, QLD 4029, Australia.
⁵⁰ Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB T2N 2T9, Canada.
⁵¹ Department of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, University of São Paulo, São Paulo 14049-900, Brazil.
⁵² Division of Hematology/Oncology, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
⁵³ Divison of Pathology, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon 1649-035, Portugal.
⁵⁴ Division of Neurosurgery, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon 1649-035, Portugal.
⁵⁵ Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
⁵⁶ Department of Pediatric Neurosurgery, Catholic University Medical School, Rome 00198, Italy.
⁵⁷ Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
⁵⁸ Kolling Institute of Medical Research, The University of Sydney, Sydney, NSW 2065, Australia.
⁵⁹ Department of Neurosurgery, Kumamoto University Graduate School of Medical Science, Kumamoto 860-8555, Japan.
⁶⁰ Division of Pediatric Neurosurgery, Department of Neurosurgery, Saint Louis University School of Medicine, St. Louis, MO, USA.
⁶¹ Department of Pathology, Hospital Infantil de Mexico Federico Gomez, Mexico City 06720, Mexico.
⁶² Department of Neurosurgery, Hospital Infantil de Mexico Federico Gomez, Mexico City 06720, Mexico.
⁶³ Division of Pediatric Neurosurgery, Rainbow & Babies Children's Hospital, Case Western Reserve, Cleveland, OH 44106, USA.
⁶⁴ Division of Haematology / Oncology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁶⁵ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Division of Haematology / Oncology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁶⁶ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Division of Pathology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁶⁷ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁶⁸ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A1, Canada; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁶⁹ The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Banting and Best Department of Medical Research, University of Toronto, Toronto, ON M5G 1L6, Canada; McLaughlin Centre, University of Toronto, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Samuel Lunenfeld Research Institute at Mount Sinai Hospital, University of Toronto, Toronto, ON M5G 1X5, Canada.
⁷⁰ Department of Computer Science, University of Toronto, Toronto, ON M5S 2E4, Canada; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada. Electronic address: anna.goldenberg@utoronto.ca.
⁷¹ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Division of Haematology / Oncology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Program in Neuroscience and Mental Health and Division of Neurology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada. Electronic address: vijay.ramaswamy@sickkids.ca.
⁷² The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A1, Canada; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada. Electronic address: mdtaylor@sickkids.ca.

PMID: 28609654
PMCID: PMC6163053
DOI: 10.1016/j.ccell.2017.05.005

Abstract

While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.

Keywords: copy number; gene expression; integrative clustering; medulloblastoma; methylation; subgroups.

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Figures

**Figure 1. Clear Separation of the Four Medulloblastoma Subgroups through Integrative SNF Clustering**
(A) Tumor clusters obtained by spectral clustering (for k = 2 to 8 groups) on the SNF network fused data obtained from both gene expression and DNA methylation data on 763 primary medulloblastomas. Relationships between tumors are indicated by the gray bars between columns. k = 4 (red box), defines the four recognized subgroups. (B) Network representation of the relationships between tumors (k = 4). The shorter the edge between samples (nodes) is the more similar the samples are (only edges with a similarity value above the median value of all patient to patient similarity values are displayed). (C) Heatmap representation of the sample-to-sample fused network data sorted by cluster for k = 4. Sample similarity is represented by red (less similar) to yellow (more similar) coloring inside the heatmap. (D) Venn diagram showing the number of samples intermediate between groups 3 and 4 when using k-means or NMF clustering method on just expression or just methylation datasets of group 3 and 4 tumors (n = 470) between k = 2 and 3. (E) Tumor clusters obtained through spectral clustering on the SNF network fused data of group 3 and 4 samples (n = 470). A small minority of samples (n = 13, 2.8%) that were initially classified as group 3 samples at k = 2, subsequently move to group 4 at k = 3. Only 3/470 (0.64%) samples remain in group 4 after k = 5. These samples are tracked up to k = 8 (orange). See also Figures S1, S3 and Table S1.

**Figure 2. Differential Set of Associated Genes and Methylation Probes across the 12 Subtypes**
(A and B) Heatmap of the top 1% most associated genes (A) and the top 1% most associated methylation probes (B) for the subtypes inside each subgroup (left side color bar), respectively. Top color bars indicate the subgroup and subtype sample affiliation. Samples are ordered by subtype. (C) Percentage of genes associated for each subgroup; (1) that have methylation probes in their promoter region, (2) for which those methylation probes are in the top 1% associated probes of the respective subgroup, and (3) for which an anti-correlation can be detected between the gene expression and methylation probes levels inside the subgroup. The numbers of genes in each category are indicated. See also Figure S2 and Tables S2 and S3.

**Figure 3. Clinical and Genomic Characteristics between Four SHH Medulloblastoma Subtypes**
(A) Network representation map of k = 4 SNF-derived subtypes. (B) Age at diagnosis for SHH subtypes at k = 4 (Kruskal-Wallis test). Boxplot center lines show data median; box limits indicate the 25^th and 75^th percentiles; lower and upper whiskers extend 1.5 times the interquartile range (IQR) from the 25^th and 75^th percentiles, respectively. Outliers are represented by individual points. (C) Overall survival of SHH subtypes (log rank test). + indicates censored cases. (D) Frequency and significance of broad cytogenetic events across the four SHH subtypes. Darker bars show significant arm-level copy-number event (q ≤ 0.1, chi-square test). * indicates key statistically significant arm gain or deletion. (E) Distribution of *TP53* mutations across SHH subtypes (Pearson’s chi-square test). (F) Overall survival stratified by *TP53* mutation within SHH α and non-SHH α (log rank test). + indicates censored cases. (G) Incidence of metastatic dissemination at diagnosis across the four SHH subtypes (chi-square test). (H) WHO histological classification at diagnosis across the four SHH subtypes (chi-square test). (I) Overall survival within SHH γ stratified by MBEN histology (log rank test). + indicates censored cases. (J) Distribution of *TERT* promoter mutations across SHH subtypes (Pearson’s chi-square test). See also Figures S4, S5; Tables S2, S4, and S5.

**Figure 4. Clinical and Genomic Characteristics between Two WNT Medulloblastoma Subtypes**
(A) Network representation map of k = 2 SNF-derived subtypes. (B) Age at diagnosis for WNT subtypes at k = 2 (Mann-Whitney U test). Boxplot center lines show data median; box limits indicate the 25^th and 75^th percentiles; lower and upper whiskers extend 1.5 times the interquartile range (IQR) from the 25^th and 75^th percentiles, respectively. Outliers are represented by individual points. (C) Overall survival comparing WNT α with WNT β (log rank test). + indicates censored cases. (D) Frequency and significance of broad cytogenetic events across the two WNT subtypes. Darker bars show significant arm-level copy-number events (q ≤ 0.1, chi-square test). * indicates key statistically significant arm gain or deletion. See also Figure S6.

**Figure 5. Clinical and Genomic Characteristics between Three Group 3 Medulloblastoma Subtypes**
(A) Network representation map of k = 3 SNF-derived subtypes. (B) Age at diagnosis of group 3 subtypes at k = 3 (Kruskal-Wallis test). Boxplot center lines show data median; box limits indicate the 25^th and 75^th percentiles; lower and upper whiskers extend 1.5 times the interquartile range (IQR) from the 25^th and 75^th percentiles, respectively. Outliers are represented by individual points. (C) Overall survival of group 3 subtypes (log rank test). + indicates censored cases. (D) Incidence of metastatic dissemination at diagnosis for the three group 3 subtypes (chi-square test). (E) Frequency and significance of broad cytogenetic events across the group 3 subtypes. Darker bars show significant arm-level events (q ≤ 0.1, chi-square test). * indicates key statistically significant arm gain or deletion. (F) Distribution of *MYC* amplifications across group 3 subtypes (Pearson’s chi-square test). (G) Overall survival of group 3 subtypes without *MYC* amplifications for each subtype compared with *MYC*-amplified tumors (log rank test). + indicates censored cases. See also Figures S6 and S7; Tables S2 and S4.

**Figure 6. Clinical and Genomic Characteristics of the Three Group 4 Medulloblastoma Subtypes**
(A) Network representation map of k = 3 SNF-derived subtypes. (B) Age at diagnosis of group 4 subtypes at k = 3 (Kruskal-Wallis test). Boxplot center lines show data median; box limits indicate the 25^th and 75^th percentiles; lower and upper whiskers extend 1.5 times the interquartile range (IQR) from the 25^th and 75^th percentiles, respectively. Outliers are represented by individual points. (C) Overall survival of group 4 subtypes (log rank test). + indicates censored cases. (D) Incidence of metastatic dissemination at diagnosis across the three group 4 subtypes (chi-square test). (E) Frequency and significance of broad cytogenetic events across the three group 4 subtypes. * indicates key statistically significant arm gain or deletion. Darker bars show significant arm-level events (q ≤ 0.1, chi-square test). See also Figure S8 and Tables S2, S4.

**Figure 7. Subtype-Enriched Pathways**
(A–D) Enrichment maps representing biological processes and pathways enriched in subtype-specific upregulated genes for SHH subtypes (A), group 3 subtypes (B), group 4 subtypes (C), and WNT subtypes (D). Each node represents a process or pathway; nodes with many shared genes are grouped and labeled by biological theme. Processes and pathways connected at edges have genes in common. Nodes are colored according to the subtype(s) in which the process is enriched; processes enriched in more than one subtype have multiple colors. Nodes sizes are proportional to the number of genes in each process, in each subgroup. Enriched processes were determined with g:Profiler (FDR-corrected q value < 0.05) and visualized with the Enrichment Map app in Cytoscape. Connected nodes and unconnected but actionable nodes are shown.

**Figure 8. Graphical Summary of the 12 Medulloblastoma Subtypes**
Schematic representation of key clinical data, copy-number events, and relationship between the subtypes inside each of the four medulloblastoma subgroups. The percentages of patients presenting with metastases and the 5-year survival percentages are presented. The age groups are: infant 0–3 years, child >3–10 years, adolescent >10–17 years, and adult >17 years.

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From One to Many: Further Refinement of Medulloblastoma Subtypes Offers Promise for Personalized Therapy.
Bavle A, Parsons DW. Bavle A, et al. Cancer Cell. 2017 Jun 12;31(6):727-729. doi: 10.1016/j.ccell.2017.05.013. Cancer Cell. 2017. PMID: 28609651

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Intertumoral Heterogeneity within Medulloblastoma Subgroups

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