期刊
NATURE
卷 529, 期 7586, 页码 351-+出版社
NATURE PORTFOLIO
DOI: 10.1038/nature16478
关键词
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资金
- Genome Canada
- Genome BC
- Terry Fox Research Institute
- Ontario Institute for Cancer Research
- Pediatric Oncology Group Ontario
- Funds from 'The Family of Kathleen Lorette'
- Clark H. Smith Brain Tumour Centre
- Montreal Children's Hospital Foundation
- Hospital for Sick Children
- Sonia and Arthur Labatt Brain Tumour Research Centre
- Chief of Research Fund
- Cancer Genetics Program
- Garron Family Cancer Centre
- B.R.A.I.N. Child
- BC Childhood Cancer Parents Association
- Stand Up To Cancer St. Baldrick's Pediatric Dream Team Translational Research Grant [SU2C-AACR-DT1113]
- Canadian Cancer Society Research Institute
- Garron Family Chair in Childhood Cancer Research
- Cure Search for Children's Cancer Foundation
- National Institutes of Health [R01CA148699, R01CA159859, CA163722, NS096236]
- Pediatric Brain Tumour Foundation
- Brainchild and The McLaughlin Centre at the University of Toronto
- Swifty Foundation
- Davis M. Ferguson Memorial Fund at ABTA
- V.R
- Ontario Institute for Cancer Research through Government of Ontario
- CureSearch for Children's Cancer
- German Cancer Aid [109252]
- German Federal Ministry of Education and Research (BMBF) [01KU1201A, 0315416C, NGFNplus 01GS0883]
- German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung)
- Hungarian Brain Research Program Grant [KTIA_13_NAP-A-V/3, NAP-A-II/7]
- Janos Bolyai scholarship of the Hungarian Academy of Sciences
- St. Baldrick's Foundation
- Cure Childhood Cancer Foundation
- B.R.A.I.N. Child and Megan's Walk
- Dr. Mildred Scheel Foundation
- Stephen Buttrum Brain Tumour Research Fellowship
- CIHR fellowship
- Alberta Innovates-Health Solutions Clinical Fellowship
- Cancer Research UK [13457] Funding Source: researchfish
- Sparks Charity [09NCL02] Funding Source: researchfish
- The Brain Tumour Charity [16/193] Funding Source: researchfish
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.
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