Chromosomal Aneuploidy in Normal, Non-Neuronal Brain Nuclei of Glioblastoma Patients is Not a Cancer Driver

Abstract Aneuploidy is a hallmark of cancers, including high-grade glioma (GBM), one of the most aggressive brain tumors. To assess whether increased aneuploidy already occurs in normal brain tissue of GBM patients, we performed single-nucleus whole-genome sequencing on 225 non-neuronal cortical nuclei from 12 disease-free individuals and 6 GBM patients, in the latter analyzing both tumor and non-tumor distal regions. Somatic aneuploidy was found in approximately 15% of non-neuronal nuclei in the adult human cortex, with recurrent chromosome 16p aneuploidy in up to 4% of nuclei. In contrast, about 51% of GBM tumor nuclei showed frequent aneuploidy of chromosomes 7 and 10, consistent with known GBM profiles. Notably, non-tumor brain regions from GBM patients exhibited aneuploidy frequencies and patterns similar to controls, including recurrent 16p involvement. These findings indicate that somatic aneuploidy in non-neuronal cells is a normal feature of the adult human brain and not linked to increased GBM risk.