Genomic profiles of low-grade murine gliomas evolve during progression to glioblastoma

Neuro Oncol. 2017 Sep 1;19(9):1237-1247. doi: 10.1093/neuonc/nox050.


Background: Gliomas are diverse neoplasms with multiple molecular subtypes. How tumor-initiating mutations relate to molecular subtypes as these tumors evolve during malignant progression remains unclear.

Methods: We used genetically engineered mouse models, histopathology, genetic lineage tracing, expression profiling, and copy number analyses to examine how genomic tumor diversity evolves during the course of malignant progression from low- to high-grade disease.

Results: Knockout of all 3 retinoblastoma (Rb) family proteins was required to initiate low-grade tumors in adult mouse astrocytes. Mutations activating mitogen-activated protein kinase signaling, specifically KrasG12D, potentiated Rb-mediated tumorigenesis. Low-grade tumors showed mutant Kras-specific transcriptome profiles but lacked copy number mutations. These tumors stochastically progressed to high-grade, in part through acquisition of copy number mutations. High-grade tumor transcriptomes were heterogeneous and consisted of 3 subtypes that mimicked human mesenchymal, proneural, and neural glioblastomas. Subtypes were confirmed in validation sets of high-grade mouse tumors initiated by different driver mutations as well as human patient-derived xenograft models and glioblastoma tumors.

Conclusion: These results suggest that oncogenic driver mutations influence the genomic profiles of low-grade tumors and that these, as well as progression-acquired mutations, contribute strongly to the genomic heterogeneity across high-grade tumors.

Keywords: genetically engineered mouse; glioblastoma; glioma; progression; transcriptome.

MeSH terms

  • Animals
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / pathology*
  • Cell Transformation, Neoplastic / genetics
  • Disease Progression
  • Genomics / methods
  • Glioblastoma / genetics*
  • Glioblastoma / pathology*
  • Glioma / genetics*
  • Glioma / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mutation