Abstract
Low-level driver mutations in subventricular zone (SVZ) cells are sufficient to induce glioblastoma.
Major finding: Low-level driver mutations in subventricular zone (SVZ) cells are sufficient to induce glioblastoma.
Approach: Sequencing of matched glioblastoma, tumor-free SVZ, and normal cortex samples reveals the cell of origin.
Impact: Neural stem cells in the SVZ with low-level mutations are likely the cell of origin in glioblastoma.
Glioblastoma (GBM) has been suggested to arise from neural stem cells (NSC) in the subventricular zone (SVZ) of the adult human brain. However, this has not been demonstrated directly in patients with GBM. To identify the cell of origin in GBM, Lee and colleagues performed deep sequencing of triple-matched tissue derived from tumor tissue, matched normal SVZ tissue, and matched normal cortical tissue or blood from 28 patients with IDH–wild-type GBM or other types of brain tumors. The tumors harbored an average of 80.7 somatic mutations, the tumor-free SVZ specimens had an average of 23 somatic mutations, and the normal brain or blood tissue contained an average of 4.3 somatic mutations. In 9 of 16 patients (56.3%) with wild-type IDH GBM, the normal SVZ contained low-level GBM driver mutations in the TERT promoter or in cancer driving genes (including EGFR, PTEN, or TP53) that were enriched in their matching tumors. Together with single-cell sequencing, these results demonstrated that SVZ cells clonally evolve into GBM. To determine if low-level SVZ mutations could result in GBM, Trp53, Pten, and Egfr low-level somatic mutations were introduced in mice into NSCs from the SVZ. The recurrent driver mutations were sufficient to induce GBM, with the mutant SVZ cells migrating to the dorsolateral caudal cortex to develop into malignant glioma. Collectively, these findings suggest that GBM arises from NSCs in the SVZ that acquire driver mutations and migrate to the site of gliomagenesis.
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