Abstract
Recent characterization of spatiotemporal genomic architecture of IDH-wild-type multifocal glioblastomas (M-GBMs) suggests a clinically unobserved common-ancestor (CA) with a less aggressive phenotype, generating highly genetically divergent malignant gliomas/GBMs in distant brain regions. Using serial MRI/3D-reconstruction, whole-genome sequencing and spectral karyotyping-based single-cell phylogenetic tree building, we show two distinct types of tumor evolution in p53-mutant driven mouse models. Malignant gliomas/GBMs grow as a single mass (Type 1) and multifocal masses (Type 2), respectively, despite both exhibiting loss of Pten/chromosome 19 (chr19) and PI3K/Akt activation with sub-tetraploid/4N genomes. Analysis of early biopsied and multi-segment tumor tissues reveals no evidence of less proliferative diploid/2N lesions in Type 1 tumors. Strikingly, CA-derived relatively quiescent tumor precursors with ancestral diploid/2N genomes and normal Pten/chr19 are observed in the subventricular zone (SVZ), but are distantly segregated from multi focal Type 2 tumors. Importantly, PI3K/Akt inhibition by Rictor/mTORC2 deletion blocks distant dispersal, restricting glioma growth in the SVZ.
Highlights
Recent characterization of spatiotemporal genomic architecture of isocitrate dehydrogenase 1/2 (IDH)-wild-type multifocal glioblastomas (M-GBMs) suggests a clinically unobserved common-ancestor (CA) with a less aggressive phenotype, generating highly genetically divergent malignant gliomas/GBMs in distant brain regions
To develop GBM models with an evolutionary pattern similar to human cancer, we constructed a series of p53 conditional knockout (CKO) models for GBM driven by a neural-specific Cre driver under control of the human GFAP promoter (Fig. 1a and Supplementary Fig. 1a)
We found no somatic mutation in Idh[1], Idh[2], or H3f3a in malignant gliomas and GBMs from all three models, which were more similar to the human IDH-wild type (WT) GBMs without exhibiting G-CIMP (Fig. 1g and Supplementary Fig. 1k, l)[22,24]
Summary
Recent characterization of spatiotemporal genomic architecture of IDH-wild-type multifocal glioblastomas (M-GBMs) suggests a clinically unobserved common-ancestor (CA) with a less aggressive phenotype, generating highly genetically divergent malignant gliomas/GBMs in distant brain regions. A recent study demonstrated that the subventricular zone (SVZ)—the largest source of neural stem cells in the adult brain—contained cells with low-level driver mutations that were shared with GBMs clinically manifested in distant brain regions[14,19]. This phenomenon was observed in over half of individuals with IDH-WT GBMs, but not in other types of brain tumors[14].
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