Journal
NATURE
Volume 576, Issue 7785, Pages 112-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-019-1775-1
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Funding
- National Brain Tumor Society
- Cancer Center Support grants [P30CA16672, P30CA034196]
- Cancer Prevention & Research Institute of Texas (CPRIT) [R140606]
- Agilent Technologies
- National Institutes of Health-National Cancer institute [NCI CA170278, NCI R01CA222146, NCI R01CA230031, NCI R01CA188288, R01CA179044, U54CA193313]
- Sidney Driscol Neuroscience Foundation
- Leeds Charitable Foundation [9R11/14-11]
- University of Leeds [11001061, 11061191]
- Leeds Teaching Hospitals NHS Trust
- PPR Foundation
- University of Leeds
- Brain Tumour Charity [10/136, GN-000580, 200450]
- EKFS [2015_Kolleg_14]
- Strain for the Brain, Milwaukee, WI
- Boehringer Ingelheim Fonds
- German National Academic Foundation
- Austrian Science Fund [KLI394]
- German Ministry of Education and Research (BMBF) [031A425]
- German Cancer Aid (DKH) [70-3163-Wi 3]
- KWF/Dutch Cancer Society [11026]
- National Institute of Neurological Disorders and Stroke [NINDS R01NS094615]
- Jane Coffin Childs Memorial Fund for Medical Research
- JAX Scholar program
- National Cancer Institute [K99 CA226387]
- American Cancer Society [130984-PF-17-141-01-DMC]
- [R01CA218144]
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The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear(12). Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, where as there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar overtime, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrentgliomas. Collectively, our results suggest that the strongest selective pressures occur during earlyglioma development and that current therapies shape this evolution in a largely stochastic manner.
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