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Divergent clonal selection dominates medulloblastoma at recurrence

Lookup NU author(s): Professor Simon Bailey, Dr Janet Lindsey, Professor Steven Clifford

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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.


Publication metadata

Author(s): Morrissy AS, Garzia L, Shih DJH, Zuyderduyn S, Huang X, Skowron P, Remke M, Cavalli FMG, Ramaswamy V, Lindsay PE, Jelveh S, Donovan LK, Wang X, Luu B, Zayne K, Li YS, Mayoh C, Thiessen N, Mercier E, Mungall KL, Ma Y, Tse K, Zeng T, Shumansky K, Roth AJL, Shah S, Farooq H, Kijima N, Holgado BL, Lee JJY, Matan-Lithwick S, Liu J, Mack SC, Manno A, Michealraj KA, Nor C, Peacock J, Qin L, Reimand J, Rolider A, Thompson YY, Wu XC, Pugh T, Ally A, Bilenky M, Butterfield YSN, Carlsen R, Cheng Y, Chuah E, Corbett RD, Dhalla N, He A, Lee D, Li HYI, Long W, Mayo M, Plettner P, Qian JQ, Schein JE, Tam A, Wong T, Birol I, Zhao YJ, Faria CC, Pimentel J, Nunes S, Shalaby T, Grotzer M, Pollack IF, Hamilton RL, Li XN, Bendel AE, Fults DW, Walter AW, Kumabe T, Tominaga T, Collins VP, Cho YJ, Hoffman C, Lyden D, Wisoff JH, Garvin JH, Stearns DS, Massimi L, Schuller U, Sterba J, Zitterbart K, Puget S, Ayrault O, Dunn SE, Tirapelli DPC, Carlotti CG, Wheeler H, Hallahan AR, Ingram W, MacDonald TJ, Olson JJ, Van Meir EG, Lee JY, Wang KC, Kim SK, Cho BK, Pietsch T, Fleischhack G, Tippelt S, Ra YS, Bailey S, Lindsey JC, Clifford SC, Eberhart CG, Cooper MK, Packer RJ, Massimino M, Garre ML, Bartels U, Tabori U, Hawkins CE, Dirks P, Bouffet E, Rutka JT, Wechsler-Reya RJ, Weiss WA, Collier LS, Dupuy AJ, Korshunov A, Jones DTW, Kool M, Northcott PA, Pfister SM, Largaespada DA, Mungall AJ, Moore RA, Jabado N, Bader GD, Jones SJM, Malkin D, Marra MA, Taylor MD

Publication type: Article

Publication status: Published

Journal: Nature

Year: 2016

Volume: 529

Issue: 7586

Pages: 351-357

Print publication date: 21/01/2016

Online publication date: 13/01/2016

Acceptance date: 23/11/2015

ISSN (print): 0028-0836

ISSN (electronic): 1476-4687

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/nature16478

DOI: 10.1038/nature16478


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Funding

Funder referenceFunder name
BC Childhood Cancer Parents Association
Brainchild and The McLaughlin Centre at the University of Toronto
Cancer Genetics Program
Chief of Research Fund
Cure Childhood Cancer Foundation
Dr. Mildred Scheel Foundation
Genome BC
Janos Bolyai scholarship of the Hungarian Academy of Sciences
Montreal Children's Hospital Foundation
Ontario Institute for Cancer Research
Ontario Institute for Cancer Research through Government of Ontario
Pediatric Brain Tumour Foundation
Pediatric Oncology Group Ontario
Stephen Buttrum Brain Tumour Research Fellowship
Alberta Innovates-Health Solutions Clinical Fellowship
B.R.A.I.N. Child
B.R.A.I.N. Child and Megan's Walk
Canadian Cancer Society Research Institute
CIHR fellowship
Clark H. Smith Brain Tumour Centre
Cure Search for Children's Cancer Foundation
CureSearch for Children's Cancer
Davis M. Ferguson Memorial Fund at ABTA
Funds from 'The Family of Kathleen Lorette'
Garron Family Cancer Centre
Garron Family Chair in Childhood Cancer Research
Genome Canada
German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung)
Hospital for Sick Children
Sonia and Arthur Labatt Brain Tumour Research Centre
St. Baldrick's Foundation
Swifty Foundation
Terry Fox Research Institute
V.R
01KU1201AGerman Federal Ministry of Education and Research (BMBF)
0315416CGerman Federal Ministry of Education and Research (BMBF)
109252German Cancer Aid
CA163722National Institutes of Health
KTIA_13_NAP-A-V/3Hungarian Brain Research Program Grant
NGFNplus 01GS0883German Federal Ministry of Education and Research (BMBF)
NAP-A-II/7Hungarian Brain Research Program Grant
R01CA148699National Institutes of Health
R01CA159859National Institutes of Health
NS096236National Institutes of Health
SU2C-AACR-DT1113Stand Up To Cancer St. Baldrick's Pediatric Dream Team Translational Research Grant

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