Intertumoral Heterogeneity within Medulloblastoma Subgroups

Florence M G Cavalli; Marc Remke; Ladislav Rampasek; John Peacock; David J H Shih; Betty Luu; Livia Garzia; Jonathon Torchia; Carolina Nor; A Sorana Morrissy; Sameer Agnihotri; Yuan Yao Thompson; Claudia M Kuzan-Fischer; Hamza Farooq; Keren Isaev; Craig Daniels; Byung-Kyu Cho; Seung-Ki Kim; Kyu-Chang Wang; Ji Yeoun Lee; Wieslawa A Grajkowska; Marta Perek-Polnik; Alexandre Vasiljevic; Cecile Faure-Conter; Anne Jouvet; Caterina Giannini; Amulya A Nageswara Rao; Kay Ka Wai Li; Ho-Keung Ng; Charles G Eberhart; Ian F Pollack; Ronald L Hamilton; G Yancey Gillespie; James M Olson; Sarah Leary; William A Weiss; Boleslaw Lach; Lola B Chambless; Reid C Thompson; Michael K Cooper; Rajeev Vibhakar; Peter Hauser; Marie-Lise C van Veelen; Johan M Kros; Pim J French; Young Shin Ra; Toshihiro Kumabe; Enrique López-Aguilar; Karel Zitterbart; Jaroslav Sterba; Gaetano Finocchiaro; Maura Massimino; Erwin G Van Meir; Satoru Osuka; Tomoko Shofuda; Almos Klekner; Massimo Zollo; Jeffrey R Leonard; Joshua B Rubin; Nada Jabado; Steffen Albrecht; Jaume Mora; Timothy E Van Meter; Shin Jung; Andrew S Moore; Andrew R Hallahan; Jennifer A Chan; Daniela P C Tirapelli; Carlos G Carlotti; Maryam Fouladi; José Pimentel; Claudia C Faria; Ali G Saad; Luca Massimi; Linda M Liau; Helen Wheeler; Hideo Nakamura; Samer K Elbabaa; Mario Perezpeña-Diazconti; Fernando Chico Ponce de León; Shenandoah Robinson; Michal Zapotocky; Alvaro Lassaletta; Annie Huang; Cynthia E Hawkins; Uri Tabori; Eric Bouffet; Ute Bartels; Peter B Dirks; James T Rutka; Gary D Bader; Jüri Reimand; Anna Goldenberg; Vijay Ramaswamy; Michael D Taylor

doi:10.1016/j.ccell.2017.05.005

Intertumoral Heterogeneity within Medulloblastoma Subgroups

Cancer Cell. 2017 Jun 12;31(6):737-754.e6. doi: 10.1016/j.ccell.2017.05.005.

Authors

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: [email protected].
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: [email protected].
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: [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Cluster Analysis
Cohort Studies
DNA Copy Number Variations
DNA Methylation
Gene Expression Profiling
Genomics
Humans
Medulloblastoma / classification*
Medulloblastoma / genetics
Medulloblastoma / therapy
Precision Medicine*

Abstract

Publication types

MeSH terms

Grants and funding