Abstract

Abstract The subventricular zone (SVZ), a neurogenic niche in the adult brain, is suspected to harbor neural stem cells (NSCs) that can acquire cancer-driving mutations and give rise to glioblastoma (GBM). Nevertheless, the corroborating genetic data are restricted to a small patient cohort. This study aimed to validate the presence of low-level oncogenic mutations in the SVZ of GBM patients and assess their clinical implications.. We performed deep hybrid capture sequencing of 15 GBM-associated genes and TERT promoter amplicon sequencing on triple-matched samples from the SVZ, primary tumor, and blood of 60 GBM patients. Approximately 62% of patients (40 of 61 patients) showed shared oncogenic mutations between the tumor and tumor-free SVZ, including TERT promoter, PTEN, and TP53. While shared mutations did not affect overall clinical profiles, TERT promoter mutations were significantly enriched in the shared group (94.9% of patients, p ≤ 0.001). RNA sequencing revealed upregulation of proliferation-related genes in tumors with shared SVZ mutations, and these patients had worse progression-free and overall survival (p = 0.038 and 0.031, respectively). This study provides the largest-scale genetic validation of the SVZ as a potential cellular origin of GBM, highlighting the distinct genetic and clinical features associated with shared oncogenic mutations. These findings warrant further investigation into the role of SVZ mutations in GBM genesis and their potential as therapeutic targets.