title: Divergent clonal selection dominates medulloblastoma at recurrence.
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.
authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 0A4, Canada.
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authors.affiliation: The Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 0A4, Canada.
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 0A4, Canada.|Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario M5S 3E1, Canada.
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 0A4, Canada.
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, Canada.
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authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, Canada.
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 0A4, Canada.
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Center for Stem Cell &Regenerative Medicine, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 0A4, Canada.
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|The Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 0A4, Canada.
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authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, Canada.
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authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, Canada.
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authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, Canada.
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authors.forename: Cynthia E
authors.initials: CE
authors.lastname: Hawkins
authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario M5S 3E1, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Dirks
authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Haematology &Oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Bouffet
authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 0A4, Canada.|Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario M5S 3E1, Canada.
authors.forename: James T
authors.initials: JT
authors.lastname: Rutka
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wechsler-Reya
authors.affiliation: Departments of Pediatrics, Neurology and Neurosurgery, University of California San Francisco, San Francisco, California 94158, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
authors.affiliation: School of Pharmacology, University of Wisconsin, Madison, Wisconsin 53715, USA.
authors.forename: Lara S
authors.initials: LS
authors.lastname: Collier
authors.affiliation: Molecular &Cellular Biology Program, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Dupuy
authors.affiliation: Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: David T W
authors.initials: DT
authors.lastname: Jones
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.|Department of Pediatric Oncology, University Hospital Heidelberg, Heidelberg 69120, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Largaespada
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, Canada.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Mungall
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, Canada.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Moore
authors.affiliation: Division of Hematology/Oncology, McGill University, Montreal, Quebec H2W 1S6., Canada.
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.affiliation: The Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada.|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, Canada.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Bader
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.|Department of Molecular Biology &Biochemistry, Simon Fraser University, Burnaby, British Columbia M5G 1L7, Canada.
authors.forename: Steven J M
authors.initials: SJ
authors.lastname: Jones
authors.affiliation: Department of Haematology &Oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.|Department of Pediatrics, University of Toronto, Toronto, Ontario M5G 1X8, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Malkin
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 0A4, Canada.|Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario M5S 3E1, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
mesh_terms: D000818:Animals; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy / Q000601:surgery / Q000628:therapy*; D002999:Clone Cells / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D061888:Craniospinal Irradiation; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics; D005260:Female; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy / Q000601:surgery / Q000628:therapy*; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D061089:Radiotherapy, Image-Guided; D012641:Selection, Genetic / Q000187:drug effects*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays