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DNA methylation and somatic mutations converge on cell cycle and define similar evolutionary histories in brain tumors

The evolutionary history of tumor cell populations can be reconstructed from patterns of genetic alterations. In contrast to the stability of genetic events, epigenetic states are reversible and sensitive to the microenvironment, prompting the question whether epigenetics can be similarly used to discover tumor phylogeny. We examined the spatial and temporal dynamics of DNA methylation in a cohort of low-grade gliomas and their patient-matched recurrences. Genes upregulated through promoter hypomethylation during malignant progression to high-grade glioblastoma were enriched in cell cycle function, evolving in parallel with genetic alterations that deregulate the G1/S cell cycle checkpoint. Moreover, phyloepigenetic relationships robustly recapitulated phylogenetic patterns inferred from somatic mutations. These findings highlight widespread co-dependency of genetic and epigenetic events throughout brain tumor evolution.

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Dataset ID Description Technology Samples
EGAD00001001613 10
EGAD00001001614 26
EGAD00001001615 10
EGAD00001001616 2
EGAD00010000827 1
EGAD00010000829 70
Publications Citations
DNA Methylation and Somatic Mutations Converge on the Cell Cycle and Define Similar Evolutionary Histories in Brain Tumors.
Cancer Cell 28: 2015 307-317
162
Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment.
Cancer Cell 32: 2017 42-56.e6
966
Models of epigenetic age capture patterns of DNA methylation in glioma associated with molecular subtype, survival, and recurrence.
Neuro Oncol 20: 2018 942-953
24
MGMT promoter methylation level in newly diagnosed low-grade glioma is a predictor of hypermutation at recurrence.
Neuro Oncol 22: 2020 1580-1590
48
Glioma progression is shaped by genetic evolution and microenvironment interactions.
Cell 185: 2022 2184-2199.e16
154
Haploinsufficiency of NFKBIA reshapes the epigenome antipodal to the IDH mutation and imparts disease fate in diffuse gliomas.
Cell Rep Med 4: 2023 101082
1
The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen.
Cancer Res 84: 2024 741-756
9