Integrated genomic characterization of IDH1-mutant glioma malignant progression

Nat Genet. 2016 Jan;48(1):59-66. doi: 10.1038/ng.3457. Epub 2015 Nov 30.

Abstract

Gliomas represent approximately 30% of all central nervous system tumors and 80% of malignant brain tumors. To understand the molecular mechanisms underlying the malignant progression of low-grade gliomas with mutations in IDH1 (encoding isocitrate dehydrogenase 1), we studied paired tumor samples from 41 patients, comparing higher-grade, progressed samples to their lower-grade counterparts. Integrated genomic analyses, including whole-exome sequencing and copy number, gene expression and DNA methylation profiling, demonstrated nonlinear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways and upregulation of the FOXM1- and E2F2-mediated cell cycle transitions, as well as epigenetic silencing of developmental transcription factor genes bound by Polycomb repressive complex 2 in human embryonic stem cells. Our results not only provide mechanistic insight into the genetic and epigenetic mechanisms driving glioma progression but also identify inhibition of the bromodomain and extraterminal (BET) family as a potential therapeutic approach.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Central Nervous System Neoplasms / genetics*
  • Central Nervous System Neoplasms / pathology
  • DNA Methylation
  • Embryonic Stem Cells / metabolism
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Gene Dosage
  • Gene Expression Regulation, Neoplastic
  • Genes, myc
  • Glioma / genetics*
  • Glioma / pathology
  • Humans
  • Isocitrate Dehydrogenase / genetics*
  • Isocitrate Dehydrogenase / metabolism
  • Mutation*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism

Substances

  • FOXM1 protein, human
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors
  • NOTCH1 protein, human
  • Receptor, Notch1
  • Isocitrate Dehydrogenase
  • IDH1 protein, human
  • Phosphatidylinositol 3-Kinases