Human glioblastoma arises from subventricular zone cells with low-level driver mutations.
Level 5 - mechanism / opinion, no new human data
Translational and bench research combining human tissue molecular genetics and animal models (Level 5 by clinical CEBM criteria).
PubMed 30069053 · doi:10.1038/s41586-018-0389-3
What was done
Deep sequencing was conducted on triple-matched tissues (normal subventricular zone [SVZ] tissue distant from the tumor mass, tumor tissue, and normal cortical tissue or blood) from 28 patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) or other brain tumors. Findings were complemented by single-cell sequencing, laser microdissection of human brain specimens, and genome-edited mouse models to evaluate neural stem cell (NSC) mutation status and migration.
What was found
Normal SVZ tissue sampled away from the tumor harbored low-level GBM driver mutations (down to approximately 1% mutational burden) in 56.3% of patients with IDH wild-type GBM, which matched mutations observed at high frequency in corresponding tumor tissue. Single-cell sequencing and mouse model validation demonstrated that astrocyte-like NSCs carrying driver mutations migrate from the SVZ to distant brain regions and develop into high-grade malignant gliomas.
Why it matters
This study provides direct human genetic and experimental evidence that astrocyte-like neural stem cells in the subventricular zone are cells of origin harboring early driver mutations in IDH wild-type glioblastoma. This clarifies the initial cellular and anatomical origins of gliomagenesis.
Limits
The human sample size was modest (28 patients across multiple brain tumor categories), and SVZ driver mutations were detected in only 56.3% of IDH wild-type GBM cases, leaving the origin of the remaining cases undetermined. Direct validation of NSC migration and tumor initiation depended on mouse models rather than direct human in vivo tracking.
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