1. Genomic profiles of low-grade murine gliomas evolve during progression to glioblastoma.
- Author
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Vitucci M, Irvin DM, McNeill RS, Schmid RS, Simon JM, Dhruv HD, Siegel MB, Werneke AM, Bash RE, Kim S, Berens ME, and Miller CR
- Subjects
- Animals, Cell Transformation, Neoplastic genetics, Disease Progression, Genomics methods, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Mutation, Brain Neoplasms genetics, Brain Neoplasms pathology, Glioblastoma genetics, Glioblastoma pathology, Glioma genetics, Glioma pathology
- 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., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)
- Published
- 2017
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