Genomic Correlates of Disease Progression and Treatment Response in Prospectively Characterized Gliomas

Clin Cancer Res. 2019 Sep 15;25(18):5537-5547. doi: 10.1158/1078-0432.CCR-19-0032. Epub 2019 Jul 1.


Purpose: The genomic landscape of gliomas has been characterized and now contributes to disease classification, yet the relationship between molecular profile and disease progression and treatment response remain poorly understood.Experimental Design: We integrated prospective clinical sequencing of 1,004 primary and recurrent tumors from 923 glioma patients with clinical and treatment phenotypes.

Results: Thirteen percent of glioma patients harbored a pathogenic germline variant, including a subset associated with heritable genetic syndromes and variants mediating DNA repair dysfunctions (29% of the total) that were associated with somatic biallelic inactivation and mechanism-specific somatic phenotypes. In astrocytomas, genomic alterations in effectors of cell-cycle progression correlated with aggressive disease independent of IDH mutation status, arose preferentially in enhancing tumors (44% vs. 8%, P < 0.001), were associated with rapid disease progression following tumor recurrence (HR = 2.6, P = 0.02), and likely preceded the acquisition of alkylating therapy-associated somatic hypermutation. Thirty-two percent of patients harbored a potentially therapeutically actionable lesion, of whom 11% received targeted therapies. In BRAF-mutant gliomas, response to agents targeting the RAF/MEK/ERK signaling axis was influenced by the type of mutation, its clonality, and its cellular and genomic context.

Conclusions: These data reveal genomic correlates of disease progression and treatment response in diverse types of glioma and highlight the potential utility of incorporating genomic information into the clinical decision-making for patients with glioma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Brain Neoplasms / diagnostic imaging
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / pathology*
  • Brain Neoplasms / therapy
  • Child
  • DNA Methylation
  • DNA Modification Methylases / genetics
  • DNA Repair Enzymes / genetics
  • Disease Progression
  • Female
  • Genetic Variation*
  • Genomics* / methods
  • Germ-Line Mutation
  • Glioma / diagnostic imaging
  • Glioma / genetics*
  • Glioma / pathology*
  • Glioma / therapy
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Image Enhancement
  • Kaplan-Meier Estimate
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Models, Biological
  • Mutation
  • Precision Medicine / methods
  • Prognosis
  • Promoter Regions, Genetic
  • Treatment Outcome
  • Tumor Suppressor Proteins / genetics
  • Young Adult


  • Tumor Suppressor Proteins
  • DNA Modification Methylases
  • MGMT protein, human
  • DNA Repair Enzymes