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

Authors: Vitucci, Mark; Irvin, David M; McNeill, Robert S; Schmid, Ralf S; Simon, Jeremy M; Dhruv, Harshil D; Siegel, Marni B; Werneke, Andrea M; Bash, Ryan E; Kim, Seungchan; Berens, Michael E; Miller, C Ryan

Published In Neuro Oncol, (2017 Sep 01)

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. 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.

PubMed ID: 28398584 Exiting the NIEHS site

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

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