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Giant cell glioblastoma (GC-GBM) is a rare variant of  IDH -wt GBM histologically characterized by the presence of numerous multinucleated giant cells and molecularly considered a hybrid between  IDH -wt and  IDH -mutant GBM. The lack of an objective definition, specifying the percentage of giant cells required for this diagnosis, may account for the absence of a definite molecular profile of this variant. This study aimed to clarify the molecular landscape of GC-GBM, exploring the mutations and copy number variations of 458 cancer-related genes, tumor mutational burden (TMB), and microsatellite instability (MSI) in 39 GBMs dichotomized into having 30–49% (15 cases) or ≥ 50% (24 cases) GCs. The type and prevalence of the genetic alterations in this series was not associated with the GCs content (  10 mut/Mb, including two (5%) that harbored MSI and one with a  POLE  mutation. The frequency of  RB1  and  NF1  alterations and TMB counts were significantly higher compared to 567  IDH  wild type ( P  &lt; 0.0001;  P  = 0.0003;  P  &lt; 0.0001) and 26  IDH -mutant ( P  &lt; 0.0001;  P  = 0.0227;  P  &lt; 0.0001) GBMs in the TCGA PanCancer Atlas cohort. These findings demonstrate that the molecular landscape of GBMs with at least 30% giant cells is dominated by the impairment of  TP53/MDM2  and  PTEN/PI3K  pathways, and additionally characterized by frequent  RB1  alterations and hypermutation and by  EGFR  amplification in more aggressive cases. The high frequency of hypermutated cases suggests that GC-GBMs might be candidates for immune check-point inhibitors clinical trials.

IDH-wild type glioblastomas featuring at least 30% giant cells are characterized by frequent RB1 and NF1 alterations and hypermutation