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.

A 1 duPont Hospital for Children Wilmington Delaware 19803 USA

AP HP Department of Neurosurgery Necker Enfants Malades Hospital Université René Descartes Paris 75743 France

Brain Tumor Program Children's Cancer Center and Department of Pediatrics Baylor College of Medicine Houston Texas 77030 USA

Canada's Michael Smith Genome Sciences Centre BC Cancer Agency Vancouver British Columbia V5Z 4S6 Canada

Center for Neuropathology Ludwig Maximilians Universität Munich 81377 Germany

Center for Stem Cell and Regenerative Medicine Cleveland Clinic Foundation Cleveland Ohio 44195 USA

Children's University Hospital of Essen D 45147 Germany

Clinical Cooperation Unit Neuropathology German Cancer Research Center Heidelberg 69120 Germany

Clinical Genomics Research Program Princess Margaret Cancer Centre University Health Network Toronto Ontario 44195 Canada

Department of Haematology and Oncology The Hospital for Sick Children Toronto Ontario M5G 1X8 Canada

Department of Hematology and Medical Oncology School of Medicine and Winship Cancer Institute Emory University Atlanta Georgia 30322 USA

Department of Laboratory Medicine and Pathobiology University of Toronto Toronto Ontario M5G 0A4 Canada

Department of Medical Genetics University of British Columbia Vancouver British Columbia V6T 1Z3 Canada

Department of Molecular Biology and Biochemistry Simon Fraser University Burnaby British Columbia M5G 1L7 Canada

Department of Molecular Oncology BC Cancer Agency Vancouver British Columbia V5Z 1L3 Canada

Department of Neurological Surgery University of Pittsburgh School of Medicine Pittsburgh Pennsylvania 15224 USA

Department of Neurology Children's National Medical Center Washington DC 20010 2970 USA

Department of Neurology Vanderbilt Medical Center Nashville Tennessee 37232 8550 USA

Department of Neurosurgery Clinical Neurosciences Center University of Utah Salt Lake City Utah 84132 USA

Department of Neurosurgery Division of Pediatric Neurosurgery Seoul National University Children's Hospital Seoul 30322 South Korea

Department of Neurosurgery Kitasato University School of Medicine Sagamihara Kanagawa 252 0374 Japan

Department of Neurosurgery NYU Langone Medical Center New York New York 10016 USA

Department of Neurosurgery School of Medicine and Winship Cancer Institute Emory University Atlanta Georgia 30322 USA

Department of Neurosurgery Tohoku University Graduate School of Medicine Sendai 980 8574 Japan

Department of Neurosurgery University of Ulsan Asan Medical Center Seoul 05505 South Korea

Department of Pathology University of Cambridge Cambridge CB2 1QP UK

Department of Pathology University of Pittsburgh School of Medicine Pittsburgh Pennsylvania 15213 USA

Department of Pediatric Oncology Hematology and Clinical Immunology University Hospital Düsseldorf M5S 3E1 Germany

Department of Pediatric Oncology School of Medicine Masaryk University Brno 625 00 Czech Republic

Department of Pediatric Oncology University Hospital Heidelberg Heidelberg 69120 Germany

Department of Pediatrics Division of Pediatric Hematology Oncology and Stem Cell Transplantation Columbia University New York New York 10032 USA

Department of Pediatrics Hematology and Oncology Rainbow Babies and Children's Hospital and Department of Pediatrics Hematology and Oncology Case Western Reserve Cleveland Ohio 44106 USA

Department of Pediatrics University of Toronto Toronto Ontario M5G 1X8 Canada

Department of Radiation Oncology University of Toronto Toronto Ontario M5G 2M9 Canada

Department of Surgery and Anatomy Faculty of Medicine of Ribeirão Preto Universidade de São Paulo Brazil Rebeirao Preto São Paulo 14049 900 Brazil

Departments of Neurosurgery Neurology and Neurological Sciences Stanford University School of Medicine Stanford California 94305 USA

Departments of Oncology and Neuro Oncology University Children's Hospital of Zurich Zurich 8032 Switzerland

Departments of Pathology Ophthalmology and Oncology John Hopkins University School of Medicine Baltimore Maryland 21205 USA

Departments of Pediatrics Cell and Developmental Biology Weill Medical College of Cornell University New York New York 10065 USA

Departments of Pediatrics Neurology and Neurosurgery University of California San Francisco San Francisco California 94158 USA

Developmental and Stem Cell Biology Program The Hospital for Sick Children Toronto Ontario M5G 0A4 Canada

Division of Hematology Oncology British Columbia Children's Hospital Vancouver British Columbia V6H 3V4 Canada

Division of Hematology Oncology McGill University Montreal Quebec H2W 1S6 Canada

Division of Neurosurgery Centro Hospitalar Lisboa Norte Hospital de Santa Maria Lisbon 1649 035 Portugal

Division of Neurosurgery The Hospital for Sick Children Toronto Ontario M5S 3E1 Canada

Division of Oncology Children's Health Queensland Brisbane Queensland 4029 Australia

Division of Pathology The Hospital for Sick Children Toronto Ontario M5G 1X8 Canada

Division of Pediatric Neurooncology German Cancer Research Center Heidelberg 69120 Germany

Divison of Pathology Centro Hospitalar Lisboa Norte Hospital de Santa Maria Lisbon 1649 035 Portugal

Fondazione IRCCS Istituto Nazionale Tumori Milan 20133 Italy

Institute for Neuropathology University of Bonn D 53105 Germany

Kolling Institute of Medical Research The University of Sydney Sydney New South Wales 2065 Australia

Masonic Cancer Center University of Minnesota Minneapolis Minnesota 55455 USA

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

Molecular and Cellular Biology Program University of Iowa Iowa City Iowa 52242 USA

Northern Institute for Cancer Research Newcastle University Newcastle upon Tyne NE1 4LP UK

Pediatric Hematology Oncology Children's Hospitals and Clinics of Minnesota Minneapolis Minnesota 55404 USA

Pediatric Neuro Oncology Program School of Medicine and Winship Cancer Institute Emory University Atlanta Georgia 30307 USA

Pediatric Neurosurgery Catholic University Medical School Rome 00198 Italy

Queensland Children's Medical Research Institute Children's Health Queensland Brisbane Queensland 4029 Australia

Radiation Medicine Program Princess Margaret Cancer Centre University Health Network Toronto Ontario M5G 2M9 Canada

Sanford Burnham Medical Research Institute La Jolla California 92037 USA

School of Computing Science Simon Fraser University Burnaby British Columbia V5A 1S6 Canada

School of Pharmacology University of Wisconsin Madison Wisconsin 53715 USA

Signaling in Development and Brain Tumors CNRS UMR 3347 INSERM U1021 Institut Curie Paris Cedex 5 91405 France

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

U O Neurochirurgia Istituto Giannina Gaslini Genova 16147 Italy

Unidade de Neuro Oncologia Pediátrica Instituto Português de Oncologia de Lisboa Francisco Gentil Lisbon 1099 023 Portugal

UQ Child Health Research Centre The University of Queensland Brisbane 4029 Australia

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Nat Rev Clin Oncol. 2016 Mar;13(3):136. doi: 10.1038/nrclinonc.2016.14. PubMed

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