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Nature. 2016 Jan 21;529(7586):351-7. doi: 10.1038/nature16478. Epub 2016 Jan 13.

Divergent clonal selection dominates medulloblastoma at recurrence.

Morrissy AS1,2, Garzia L1,2, Shih DJ1,2,3, Zuyderduyn S4, Huang X1, Skowron P1,2,3, Remke M5, Cavalli FM1,2, Ramaswamy V1,2,3,6, Lindsay PE7,8, Jelveh S8, Donovan LK1,2, Wang X1,2,3, Luu B1,2, Zayne K1,2, Li Y9, Mayoh C9, Thiessen N9, Mercier E9, Mungall KL9, Ma Y9, Tse K9, Zeng T9, Shumansky K10, Roth AJ10, Shah S10, Farooq H1,2, Kijima N1,2, Holgado BL1,2, Lee JJ1,2,3, Matan-Lithwick S1,2, Liu J1,2, Mack SC1,2,11, Manno A1,2, Michealraj KA1,2, Nor C1,2, Peacock J1,2,3, Qin L1,2, Reimand J2,4, Rolider A1,2, Thompson YY1,2,3, Wu X1,2, Pugh T12, Ally A9, Bilenky M9, Butterfield YS9, Carlsen R9, Cheng Y9, Chuah E9, Corbett RD9, Dhalla N9, He A9, Lee D9, Li HI9, Long W9, Mayo M9, Plettner P9, Qian JQ9, Schein JE9, Tam A9, Wong T9, Birol I9,13,14, Zhao Y9, Faria CC15, Pimentel J16, Nunes S17, Shalaby T18, Grotzer M18, Pollack IF19, Hamilton RL20, Li XN21, Bendel AE22, Fults DW23, Walter AW24, Kumabe T25, Tominaga T26, Collins VP27, Cho YJ28, Hoffman C6, Lyden D29, Wisoff JH30, Garvin JH Jr31, Stearns DS32, Massimi L33, Schüller U34, Sterba J35, Zitterbart K35, Puget S36, Ayrault O37, Dunn SE38, Tirapelli DP39, Carlotti CG39, Wheeler H40, Hallahan AR41,42, Ingram W41,43, MacDonald TJ44, Olson JJ45, Van Meir EG46, Lee JY47, Wang KC47, Kim SK47, Cho BK47, Pietsch T48, Fleischhack G49, Tippelt S49, Ra YS50, Bailey S51, Lindsey JC51, Clifford SC51, Eberhart CG52, Cooper MK53, Packer RJ54, Massimino M55, Garre ML56, Bartels U57, Tabori U2,57, Hawkins CE2,58, Dirks P2,6, Bouffet E2,57, Rutka JT2,3,6, Wechsler-Reya RJ59, Weiss WA60, Collier LS61, Dupuy AJ62, Korshunov A63, Jones DT64, Kool M64, Northcott PA64, Pfister SM64,65, Largaespada DA66, Mungall AJ9, Moore RA9, Jabado N67, Bader GD4,68, Jones SJ9,13,69, Malkin D57,70, Marra MA9,13, Taylor MD1,2,3,6.

Author information

1
Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
2
The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
3
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 0A4, Canada.
4
The Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
5
Department of Pediatric Oncology, Hematology, and Clinical Immunology, University Hospital Düsseldorf, M5S 3E1, Germany.
6
Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario M5S 3E1, Canada.
7
Department of Radiation Oncology, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
8
Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.
9
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, Canada.
10
Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
11
Center for Stem Cell &Regenerative Medicine, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
12
Clinical Genomics Research Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario 44195, Canada.
13
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
14
School of Computing Science, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
15
Division of Neurosurgery, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon 1649-035, Portugal.
16
Divison of Pathology, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon 1649-035, Portugal.
17
Unidade de Neuro-Oncologia Pediátrica, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon 1099-023, Portugal.
18
Departments of Oncology and Neuro-Oncology, University Children's Hospital of Zurich, Zurich 8032, Switzerland.
19
Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224, USA.
20
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
21
Brain Tumor Program, Children's Cancer Center and Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
22
Pediatric Hematology-Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota 55404, USA.
23
Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah 84132, USA.
24
A I duPont Hospital for Children, Wilmington, Delaware 19803, USA.
25
Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.
26
Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
27
Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
28
Departments of Neurosurgery, Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.
29
Departments of Pediatrics, Cell &Developmental Biology, Weill Medical College of Cornell University, New York, New York 10065, USA.
30
Department of Neurosurgery, NYU Langone Medical Center, New York, New York 10016, USA.
31
Department of Pediatrics, Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Columbia University, New York, New York 10032, USA.
32
Department of Pediatrics-Hematology and Oncology, Rainbow Babies &Children's Hospital and Department of Pediatrics-Hematology and Oncology, Case Western Reserve, Cleveland, Ohio 44106, USA.
33
Pediatric Neurosurgery, Catholic University Medical School, Rome 00198, Italy.
34
Center for Neuropathology, Ludwig-Maximilians-Universität, Munich 81377, Germany.
35
Department of Pediatric Oncology, School of Medicine, Masaryk University, Brno 625 00, Czech Republic.
36
AP-HP, Department of Neurosurgery, Necker-Enfants Malades Hospital, Université René Descartes, Paris 75743, France.
37
Signaling in Development and Brain Tumors, CNRS UMR 3347 / INSERM U1021, Institut Curie, Paris Cedex 5 91405, France.
38
Division of Hematology/Oncology, British Columbia Children's Hospital, Vancouver, British Columbia V6H 3V4, Canada.
39
Department of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, Universidade de São Paulo, Brazil, Rebeirao Preto, São Paulo 14049-900, Brazil.
40
Kolling Institute of Medical Research, The University of Sydney, Sydney, New South Wales 2065, Australia.
41
Queensland Children's Medical Research Institute, Children's Health Queensland, Brisbane, Queensland 4029, Australia.
42
Division of Oncology, Children's Health Queensland, Brisbane, Queensland 4029, Australia.
43
UQ Child Health Research Centre, The University of Queensland, Brisbane 4029, Australia.
44
Pediatric Neuro-Oncology Program, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, Georgia 30307, USA.
45
Department of Neurosurgery, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
46
Department of Hematology &Medical Oncology, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
47
Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul 30322, South Korea.
48
Institute for Neuropathology, University of Bonn D-53105, Germany.
49
Children's University Hospital of Essen D-45147, Germany.
50
Department of Neurosurgery, University of Ulsan, Asan Medical Center, Seoul 05505, South Korea.
51
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, UK.
52
Departments of Pathology, Ophthalmology and Oncology, John Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
53
Department of Neurology, Vanderbilt Medical Center, Nashville, Tennessee 37232-8550, USA.
54
Department of Neurology, Children's National Medical Center, Washington DC 20010-2970, USA.
55
Fondazione IRCCS Istituto Nazionale Tumori, Milan 20133, Italy.
56
U.O. Neurochirurgia, Istituto Giannina Gaslini, Genova 16147, Italy.
57
Department of Haematology &Oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
58
Division of Pathology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
59
Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
60
Departments of Pediatrics, Neurology and Neurosurgery, University of California San Francisco, San Francisco, California 94158, USA.
61
School of Pharmacology, University of Wisconsin, Madison, Wisconsin 53715, USA.
62
Molecular &Cellular Biology Program, University of Iowa, Iowa City, Iowa 52242, USA.
63
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
64
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
65
Department of Pediatric Oncology, University Hospital Heidelberg, Heidelberg 69120, Germany.
66
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
67
Division of Hematology/Oncology, McGill University, Montreal, Quebec H2W 1S6., Canada.
68
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.
69
Department of Molecular Biology &Biochemistry, Simon Fraser University, Burnaby, British Columbia M5G 1L7, Canada.
70
Department of Pediatrics, University of Toronto, Toronto, Ontario M5G 1X8, Canada.

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.

Comment in

PMID:
26760213
PMCID:
PMC4936195
DOI:
10.1038/nature16478
[Indexed for MEDLINE]
Free PMC Article

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