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Cancer Cell. 2015 Sep 14;28(3):307-317. doi: 10.1016/j.ccell.2015.07.012.

DNA Methylation and Somatic Mutations Converge on the Cell Cycle and Define Similar Evolutionary Histories in Brain Tumors.

Author information

1
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94158, USA.
2
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA 94158, USA.
3
Department of Pathology, University of California San Francisco, San Francisco, CA 94158, USA.
4
Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
5
AP-HP, Hôpital de la Pitié Salpêtrière, Service de Neurologie 2-Mazarin, F-75013, Paris, France.
6
Department of Neurosurgery, Brain Tumor Center, Erasmus Medical Center, Rotterdam, The Netherlands.
7
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
8
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
9
Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
10
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA.
11
Department of Bioengineering, University of Illinois at Urbana-Champaign, Champaign, IL 61801, USA.
12
Department of Physics, University of Illinois at Urbana-Champaign, Champaign, IL 61801, USA.
13
Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Champaign, IL 61801, USA.
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Contributed equally

Abstract

The evolutionary history of tumor cell populations can be reconstructed from patterns of genetic alterations. In contrast to stable genetic events, epigenetic states are reversible and sensitive to the microenvironment, prompting the question whether epigenetic information can similarly be 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 transcriptionally 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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PMID:
26373278
PMCID:
PMC4573399
DOI:
10.1016/j.ccell.2015.07.012
[Indexed for MEDLINE]
Free PMC Article

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