Journal article
Divergent clonal selection dominates medulloblastoma at recurrence
Nature (London), Vol.529(7586), pp.351-357
01/21/2016
DOI: 10.1038/nature16478
PMCID: PMC4936195
PMID: 26760213
Abstract
The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.
Details
- Title: Subtitle
- Divergent clonal selection dominates medulloblastoma at recurrence
- Creators
- A Sorana Morrissy - The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, CanadaLivia Garzia - The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, CanadaDavid J H Shih - Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 0A4, CanadaScott Zuyderduyn - University of TorontoXi Huang - Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, CanadaPatryk Skowron - Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 0A4, CanadaYuan Y Thompson - Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 0A4, CanadaXiaochong Wu - The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, CanadaTrevor Pugh - Clinical Genomics Research Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario 44195, CanadaAdrian Ally - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaMikhail Bilenky - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaYaron S N Butterfield - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaMarc Remke - Department of Pediatric Oncology, Hematology, and Clinical Immunology, University Hospital Düsseldorf, M5S 3E1, GermanyRebecca Carlsen - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaFlorence M G Cavalli - The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, CanadaYoung Cheng - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaVijay Ramaswamy - Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario M5S 3E1, CanadaEric Chuah - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaRichard D Corbett - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaPatricia E Lindsay - Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, CanadaSalomeh Jelveh - Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, CanadaNoreen Dhalla - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaLaura K Donovan - The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, CanadaAn He - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaXin Wang - Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 0A4, CanadaDarlene Lee - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaBetty Luu - The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, CanadaHaiyan I Li - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaWilliam Long - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaKory Zayne - The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, CanadaYisu Li - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaMichael Mayo - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaChelsea Mayoh - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaPatrick Plettner - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaNina Thiessen - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaJenny Q Qian - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaEloi Mercier - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaJacqueline E Schein - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaAngela Tam - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaKaren L Mungall - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaTina Wong - National University of SingaporeInanc Birol - School of Computing Science, Simon Fraser University, Burnaby, British Columbia V5A 1S6, CanadaYongjun Zhao - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaClaudia C Faria - Division of Neurosurgery, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon 1649-035, PortugalJosé Pimentel - Divison of Pathology, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon 1649-035, PortugalSofia Nunes - Unidade de Neuro-Oncologia Pediátrica, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon 1099-023, PortugalTarek Shalaby - Departments of Oncology and Neuro-Oncology, University Children's Hospital of Zurich, Zurich 8032, SwitzerlandMichael Grotzer - Departments of Oncology and Neuro-Oncology, University Children's Hospital of Zurich, Zurich 8032, SwitzerlandIan F Pollack - Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224, USARonald L Hamilton - University of Illinois ChicagoXiao-Nan Li - Baylor College of MedicineAnne E Bendel - Pediatric Hematology-Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota 55404, USADaniel W Fults - Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah 84132, USAAndrew W Walter - A I duPont Hospital for Children, Wilmington, Delaware 19803, USAToshihiro Kumabe - Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, JapanTeiji Tominaga - Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, JapanV Peter Collins - Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UKYoon-Jae Cho - Departments of Neurosurgery, Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USACaitlin Hoffman - Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario M5S 3E1, CanadaDavid Lyden - Departments of Pediatrics, Cell &Developmental Biology, Weill Medical College of Cornell University, New York, New York 10065, USAJeffrey H Wisoff - Department of Neurosurgery, NYU Langone Medical Center, New York, New York 10016, USAJames H Garvin Jr - Department of Pediatrics, Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Columbia University, New York, New York 10032, USADuncan S Stearns - Department of Pediatrics-Hematology and Oncology, Rainbow Babies &Children's Hospital and Department of Pediatrics-Hematology and Oncology, Case Western Reserve, Cleveland, Ohio 44106, USALuca Massimi - Pediatric Neurosurgery, Catholic University Medical School, Rome 00198, ItalyUlrich Schüller - Center for Neuropathology, Ludwig-Maximilians-Universität, Munich 81377, GermanyJaroslav Sterba - Department of Pediatric Oncology, School of Medicine, Masaryk University, Brno 625 00, Czech RepublicKarel Zitterbart - Department of Pediatric Oncology, School of Medicine, Masaryk University, Brno 625 00, Czech RepublicStephanie Puget - AP-HP, Department of Neurosurgery, Necker-Enfants Malades Hospital, Université René Descartes, Paris 75743, FranceOlivier Ayrault - Signaling in Development and Brain Tumors, CNRS UMR 3347 / INSERM U1021, Institut Curie, Paris Cedex 5 91405, FranceSandra E Dunn - Division of Hematology/Oncology, British Columbia Children's Hospital, Vancouver, British Columbia V6H 3V4, CanadaDaniela P C Tirapelli - Department of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, Universidade de São Paulo, Brazil, Rebeirao Preto, São Paulo 14049-900, BrazilCarlos G Carlotti - Department of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, Universidade de São Paulo, Brazil, Rebeirao Preto, São Paulo 14049-900, BrazilHelen Wheeler - Kolling Institute of Medical Research, The University of Sydney, Sydney, New South Wales 2065, AustraliaAndrew R Hallahan - Division of Oncology, Children's Health Queensland, Brisbane, Queensland 4029, AustraliaWendy Ingram - UQ Child Health Research Centre, The University of Queensland, Brisbane 4029, AustraliaTobey J MacDonald - Pediatric Neuro-Oncology Program, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, Georgia 30307, USAJeffrey J Olson - Department of Neurosurgery, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USAErwin G Van Meir - Department of Hematology &Medical Oncology, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USAJi-Yeoun Lee - Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul 30322, South KoreaKyu-Chang Wang - University of Iowa, BiostatisticsSeung-Ki Kim - Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul 30322, South KoreaYusanne Ma - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaKane Tse - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaByung-Kyu Cho - Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul 30322, South KoreaThomas Zeng - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaTorsten Pietsch - Institute for Neuropathology, University of Bonn D-53105, GermanyGudrun Fleischhack - Children's University Hospital of Essen D-45147, GermanyKarey Shumansky - Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, CanadaStephan Tippelt - Children's University Hospital of Essen D-45147, GermanyAndrew J L Roth - Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, CanadaSohrab Shah - Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, CanadaYoung Shin Ra - Department of Neurosurgery, University of Ulsan, Asan Medical Center, Seoul 05505, South KoreaHamza Farooq - The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, CanadaSimon Bailey - Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, UKNoriyuki Kijima - The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, CanadaJanet C Lindsey - Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, UKBorja L Holgado - The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, CanadaSteven C Clifford - Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, UKJohn J Y Lee - Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 0A4, CanadaCharles G Eberhart - Departments of Pathology, Ophthalmology and Oncology, John Hopkins University School of Medicine, Baltimore, Maryland 21205, USAStuart Matan-Lithwick - The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, CanadaMichael K Cooper - Department of Neurology, Vanderbilt Medical Center, Nashville, Tennessee 37232-8550, USAJessica Liu - The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, CanadaRoger J Packer - Department of Neurology, Children's National Medical Center, Washington DC 20010-2970, USAStephen C Mack - Center for Stem Cell &Regenerative Medicine, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USAMaura Massimino - Fondazione IRCCS Istituto Nazionale Tumori, Milan 20133, ItalyAlex Manno - The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, CanadaMaria Luisa Garre - U.O. Neurochirurgia, Istituto Giannina Gaslini, Genova 16147, ItalyK A Michealraj - The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, CanadaUte Bartels - Department of Haematology &Oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, CanadaCarolina Nor - The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, CanadaUri Tabori - Department of Haematology &Oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, CanadaJohn Peacock - Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 0A4, CanadaCynthia E Hawkins - Division of Pathology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, CanadaLei Qin - The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, CanadaPeter Dirks - Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario M5S 3E1, CanadaJuri Reimand - The Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, CanadaEric Bouffet - Department of Haematology &Oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, CanadaAdi Rolider - The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, CanadaJames T Rutka - Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario M5S 3E1, CanadaRobert J Wechsler-Reya - Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USAWilliam A Weiss - Departments of Pediatrics, Neurology and Neurosurgery, University of California San Francisco, San Francisco, California 94158, USALara S Collier - School of Pharmacology, University of Wisconsin, Madison, Wisconsin 53715, USAAdam J Dupuy - University of Iowa, Anatomy and Cell BiologyAndrey Korshunov - Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg 69120, GermanyDavid T W Jones - Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg 69120, GermanyMarcel Kool - Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg 69120, GermanyPaul A Northcott - Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg 69120, GermanyStefan M Pfister - Department of Pediatric Oncology, University Hospital Heidelberg, Heidelberg 69120, GermanyDavid A Largaespada - Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USAAndrew J Mungall - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaRichard A Moore - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, CanadaNada Jabado - Division of Hematology/Oncology, McGill University, Montreal, Quebec H2W 1S6., CanadaGary D Bader - McLaughlin Centre and Department of Molecular Genetics, Banting and Best Department of Medical Research and Samuel Lunenfeld Research Institute at Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1L7, CanadaSteven J M Jones - Department of Molecular Biology &Biochemistry, Simon Fraser University, Burnaby, British Columbia M5G 1L7, CanadaDavid Malkin - Department of Pediatrics, University of Toronto, Toronto, Ontario M5G 1X8, CanadaMarco A Marra - Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, CanadaMichael D Taylor - Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario M5S 3E1, Canada
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.529(7586), pp.351-357
- DOI
- 10.1038/nature16478
- PMID
- 26760213
- PMCID
- PMC4936195
- NLM abbreviation
- Nature
- ISSN
- 0028-0836
- eISSN
- 1476-4687
- Publisher
- England
- Grant note
- R01CA148699 / NCI NIH HHS R01 CA159859 / NCI NIH HHS R01 NS096236 / NINDS NIH HHS R01CA159859 / NCI NIH HHS CIHR R01 CA148699 / NCI NIH HHS 13457 / Cancer Research UK R01 CA113636 / NCI NIH HHS P30 CA077598 / NCI NIH HHS P30 CA030199 / NCI NIH HHS R01 CA163722 / NCI NIH HHS
- Language
- English
- Date published
- 01/21/2016
- Academic Unit
- Anatomy and Cell Biology; Pathology
- Record Identifier
- 9984025455402771
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