Longitudinal molecular trajectories of diffuse glioma in adults

GLASS Consortium

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear1,2. 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.

Original languageEnglish
Pages (from-to)112-120
Number of pages9
JournalNature
Volume576
Issue number7785
DOIs
StatePublished - Dec 2019

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Glioma
Recurrence
Chromosome Deletion
Mutation
Survival
Alkylating Agents
Aneuploidy
DNA Sequence Analysis
Genes
Cell Cycle
Therapeutics
Phenotype
Neoplasms

Cite this

GLASS Consortium. / Longitudinal molecular trajectories of diffuse glioma in adults. In: Nature. 2019 ; Vol. 576, No. 7785. pp. 112-120.
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abstract = "The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear1,2. 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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Longitudinal molecular trajectories of diffuse glioma in adults. / GLASS Consortium.

In: Nature, Vol. 576, No. 7785, 12.2019, p. 112-120.

Research output: Contribution to journalArticle

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AU - GLASS Consortium

AU - Barthel, Floris P

AU - Johnson, Kevin C

AU - Varn, Frederick S

AU - Moskalik, Anzhela D

AU - Tanner, Georgette

AU - Kocakavuk, Emre

AU - Anderson, Kevin J

AU - Abiola, Olajide

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AU - Alfaro, Kristin D

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AU - Ashley, David M

AU - Bandopadhayay, Pratiti

AU - Barnholtz-Sloan, Jill S

AU - Beroukhim, Rameen

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AU - Brastianos, Priscilla K

AU - Brat, Daniel J

AU - Brodbelt, Andrew R

AU - Bruns, Alexander F

AU - Bulsara, Ketan R

AU - Chakrabarty, Aruna

AU - Chakravarti, Arnab

AU - Chuang, Jeffrey H

AU - Claus, Elizabeth B

AU - Cochran, Elizabeth J

AU - Connelly, Jennifer

AU - Costello, Joseph F

AU - Finocchiaro, Gaetano

AU - Fletcher, Michael N

AU - French, Pim J

AU - Gan, Hui K

AU - Gilbert, Mark R

AU - Gould, Peter V

AU - Grimmer, Matthew R

AU - Iavarone, Antonio

AU - Ismail, Azzam

AU - Jenkinson, Michael D

AU - Khasraw, Mustafa

AU - Kim, Hoon

AU - Kouwenhoven, Mathilde C M

AU - LaViolette, Peter S

AU - Li, Meihong

AU - Lichter, Peter

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AU - Lowman, Allison K

AU - Malta, Tathiane M

AU - Mazor, Tali

AU - Park, Chul-Kee

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N2 - The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear1,2. 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.

AB - The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear1,2. 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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