TP53, ATRX alterations, and low tumor mutation load feature IDH-wildtype giant cell glioblastoma despite exceptional ultra-mutated tumors

BACKGROUND: Giant cell glioblastoma (gcGBM) is a rare morphological variant of IDH-wildtype (IDHwt) GBM that occurs in young adults and have a slightly better prognosis than “classic” IDHwt GBM. METHODS: We studied 36 GBMs, 14 with a histopathological diagnosis of gcGBM and 22 with a giant cell component. We analyzed the genetic profile of the most frequently mutated genes in gliomas and assessed the tumor mutation load (TML) by gene-targeted next-generation sequencing. We validated our findings using The Cancer Genome Atlas (TCGA) data. RESULTS: p53 was altered by gene mutation or protein overexpression in all cases, while driver IDH1, IDH2, BRAF, or H3F3A mutations were infrequent or absent. Compared to IDHwt GBMs, gcGBMs had a significant higher frequency of TP53, ATRX, RB1, and NF1 mutations, while lower frequency of EGFR amplification, CDKN2A deletion, and TERT promoter mutation. Almost all tumors had low TML values. The high TML observed in only 2 tumors was consistent with POLE and MSH2 mutations. In the histopathological review of TCGA IDHwt, TP53-mutant tumors identified giant cells in 37% of the cases. Considering our series and that of the TCGA, patients with TP53-mutant gcGBMs had better overall survival than those with TP53wt GBMs (log-rank test, P < .002). CONCLUSIONS: gcGBMs have molecular features that contrast to “classic” IDHwt GBMs: unusually frequent ATRX mutations and few EGFR amplifications and CDKN2A deletions, especially in tumors with a high number of giant cells. TML is frequently low, although exceptional high TML suggests a potential for immune checkpoint therapy in some cases, which may be relevant for personalized medicine.