title: Genomic profiles of low-grade murine gliomas evolve during progression to glioblastoma.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Curriculum in Genetics and Molecular Biology, Pathobiology and Translational Science Graduate Program, Division of Neuropathology, Department of Pathology and Laboratory Medicine, Carolina Institute for Developmental Disabilities and Department of Genetics, Lineberger Comprehensive Cancer Center, Neurosciences Center, and Department of Neurology, University of North Carolina (UNC) School of Medicine, Chapel Hill, North Carolina;Cancer & Cell Biology Division, Translational Genomics Institute (TGen), Phoenix, Arizona.
authors.forename: Mark
authors.initials: M
authors.lastname: Vitucci
authors.affiliation: Curriculum in Genetics and Molecular Biology, Pathobiology and Translational Science Graduate Program, Division of Neuropathology, Department of Pathology and Laboratory Medicine, Carolina Institute for Developmental Disabilities and Department of Genetics, Lineberger Comprehensive Cancer Center, Neurosciences Center, and Department of Neurology, University of North Carolina (UNC) School of Medicine, Chapel Hill, North Carolina;Cancer & Cell Biology Division, Translational Genomics Institute (TGen), Phoenix, Arizona.
authors.forename: David M
authors.initials: DM
authors.lastname: Irvin
authors.affiliation: Curriculum in Genetics and Molecular Biology, Pathobiology and Translational Science Graduate Program, Division of Neuropathology, Department of Pathology and Laboratory Medicine, Carolina Institute for Developmental Disabilities and Department of Genetics, Lineberger Comprehensive Cancer Center, Neurosciences Center, and Department of Neurology, University of North Carolina (UNC) School of Medicine, Chapel Hill, North Carolina;Cancer & Cell Biology Division, Translational Genomics Institute (TGen), Phoenix, Arizona.
authors.forename: Robert S
authors.initials: RS
authors.lastname: McNeill
authors.affiliation: Curriculum in Genetics and Molecular Biology, Pathobiology and Translational Science Graduate Program, Division of Neuropathology, Department of Pathology and Laboratory Medicine, Carolina Institute for Developmental Disabilities and Department of Genetics, Lineberger Comprehensive Cancer Center, Neurosciences Center, and Department of Neurology, University of North Carolina (UNC) School of Medicine, Chapel Hill, North Carolina;Cancer & Cell Biology Division, Translational Genomics Institute (TGen), Phoenix, Arizona.
authors.forename: Ralf S
authors.initials: RS
authors.lastname: Schmid
authors.affiliation: Curriculum in Genetics and Molecular Biology, Pathobiology and Translational Science Graduate Program, Division of Neuropathology, Department of Pathology and Laboratory Medicine, Carolina Institute for Developmental Disabilities and Department of Genetics, Lineberger Comprehensive Cancer Center, Neurosciences Center, and Department of Neurology, University of North Carolina (UNC) School of Medicine, Chapel Hill, North Carolina;Cancer & Cell Biology Division, Translational Genomics Institute (TGen), Phoenix, Arizona.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Simon
authors.affiliation: Curriculum in Genetics and Molecular Biology, Pathobiology and Translational Science Graduate Program, Division of Neuropathology, Department of Pathology and Laboratory Medicine, Carolina Institute for Developmental Disabilities and Department of Genetics, Lineberger Comprehensive Cancer Center, Neurosciences Center, and Department of Neurology, University of North Carolina (UNC) School of Medicine, Chapel Hill, North Carolina;Cancer & Cell Biology Division, Translational Genomics Institute (TGen), Phoenix, Arizona.
authors.forename: Harshil D
authors.initials: HD
authors.lastname: Dhruv
authors.affiliation: Curriculum in Genetics and Molecular Biology, Pathobiology and Translational Science Graduate Program, Division of Neuropathology, Department of Pathology and Laboratory Medicine, Carolina Institute for Developmental Disabilities and Department of Genetics, Lineberger Comprehensive Cancer Center, Neurosciences Center, and Department of Neurology, University of North Carolina (UNC) School of Medicine, Chapel Hill, North Carolina;Cancer & Cell Biology Division, Translational Genomics Institute (TGen), Phoenix, Arizona.
authors.forename: Marni B
authors.initials: MB
authors.lastname: Siegel
authors.affiliation: Curriculum in Genetics and Molecular Biology, Pathobiology and Translational Science Graduate Program, Division of Neuropathology, Department of Pathology and Laboratory Medicine, Carolina Institute for Developmental Disabilities and Department of Genetics, Lineberger Comprehensive Cancer Center, Neurosciences Center, and Department of Neurology, University of North Carolina (UNC) School of Medicine, Chapel Hill, North Carolina;Cancer & Cell Biology Division, Translational Genomics Institute (TGen), Phoenix, Arizona.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Werneke
authors.affiliation: Curriculum in Genetics and Molecular Biology, Pathobiology and Translational Science Graduate Program, Division of Neuropathology, Department of Pathology and Laboratory Medicine, Carolina Institute for Developmental Disabilities and Department of Genetics, Lineberger Comprehensive Cancer Center, Neurosciences Center, and Department of Neurology, University of North Carolina (UNC) School of Medicine, Chapel Hill, North Carolina;Cancer & Cell Biology Division, Translational Genomics Institute (TGen), Phoenix, Arizona.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Bash
authors.affiliation: Curriculum in Genetics and Molecular Biology, Pathobiology and Translational Science Graduate Program, Division of Neuropathology, Department of Pathology and Laboratory Medicine, Carolina Institute for Developmental Disabilities and Department of Genetics, Lineberger Comprehensive Cancer Center, Neurosciences Center, and Department of Neurology, University of North Carolina (UNC) School of Medicine, Chapel Hill, North Carolina;Cancer & Cell Biology Division, Translational Genomics Institute (TGen), Phoenix, Arizona.
authors.forename: Seungchan
authors.initials: S
authors.lastname: Kim
authors.affiliation: Curriculum in Genetics and Molecular Biology, Pathobiology and Translational Science Graduate Program, Division of Neuropathology, Department of Pathology and Laboratory Medicine, Carolina Institute for Developmental Disabilities and Department of Genetics, Lineberger Comprehensive Cancer Center, Neurosciences Center, and Department of Neurology, University of North Carolina (UNC) School of Medicine, Chapel Hill, North Carolina;Cancer & Cell Biology Division, Translational Genomics Institute (TGen), Phoenix, Arizona.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Berens
authors.affiliation: Curriculum in Genetics and Molecular Biology, Pathobiology and Translational Science Graduate Program, Division of Neuropathology, Department of Pathology and Laboratory Medicine, Carolina Institute for Developmental Disabilities and Department of Genetics, Lineberger Comprehensive Cancer Center, Neurosciences Center, and Department of Neurology, University of North Carolina (UNC) School of Medicine, Chapel Hill, North Carolina;Cancer & Cell Biology Division, Translational Genomics Institute (TGen), Phoenix, Arizona.
authors.forename: C Ryan
authors.initials: CR
authors.lastname: Miller
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018450:Disease Progression; D023281:Genomics / Q000379:methods; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology*; D005910:Glioma / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation
keywords: genetically engineered mouse; glioblastoma; glioma; progression; transcriptome