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Longitudinal molecular trajectories of diffuse glioma in adults


Barthel, Floris P; Johnson, Kevin C; Varn, Frederick S; Moskalik, Anzhela D; Tanner, Georgette; Kocakavuk, Emre; et al; Weller, Michael (2019). Longitudinal molecular trajectories of diffuse glioma in adults. Nature, 576(7785):112-120.

Abstract

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear$^{1,2}$. 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, whereas 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 over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.

Abstract

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear$^{1,2}$. 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, whereas 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 over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:1 December 2019
Deposited On:08 Jan 2020 10:01
Last Modified:15 Feb 2020 02:04
Publisher:Springer
ISSN:0028-0836
OA Status:Closed
Publisher DOI:https://doi.org/10.1038/s41586-019-1775-1
PubMed ID:31748746

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Embargo till: 2020-12-01