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

Tali Mazor, Aleksandr Pankov, Brett E. Johnson, Chibo Hong, Emily G. Hamilton, Robert J.A. Bell, Ivan V. Smirnov, Gerald F. Reis, Joanna J. Phillips, Michael J. Barnes, Ahmed Idbaih, Agusti Alentorn, Jenneke J. Kloezeman, Martine L.M. Lamfers, Andrew W. Bollen, Barry S. Taylor, Annette M. Molinaro, Adam B. Olshen, Susan M. Chang, Jun S. SongJoseph F. Costello

Research output: Contribution to journalArticlepeer-review

129 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)307-317
Number of pages11
JournalCancer Cell
Volume28
Issue number3
DOIs
StatePublished - Sep 14 2015
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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