| Summary: | Background: Glioblastomas (GBMs) are classified into isocitrate dehydrogenase (<i>IDH)</i> mutants and <i>IDH</i> wild-types (<i>IDH</i>-wt). This study aimed at identifying the mutational assets of <i>IDH</i>-wt GBMs in patients aged 18−54 years for which limited data are available. Methods: Sixteen <i>IDH</i>-wt GBMs from adults < 55 years old were explored for mutations, copy number variations, tumour mutational load (TML), and mutational spectrum by a 409 genes TML panel. Results: Eight (50%) <i>IDH</i>-wt GBMs were hypermutated (TML > 9 mutations/Mb) and two (12.5%) were ultra-mutated (TML > 100 mutations/Mb). One ultra-mutated GBM had microsatellite instability (MSI), a somatic <i>MSH6</i> mutation, and a germline <i>POLE</i> mutation. The other ultra-mutated GBMs had MSI and two somatic mutations in <i>MSH2</i>. Both ultra-mutated GBMs featured at least 25% giant cells. The overall survival of eight patients with hypermutated GBMs was significantly longer than that of patients with non-hypermutated GBMs (<i>p</i> = 0.04). Conclusions: We identified a hyper-mutated subgroup among <i>IDH</i>-wt GBMs in adults < 55 years that had improved prognosis. Two cases were ultra-mutated and characterized by the presence of at least 25% giant cells, MMR mutations, and MSI. Since high TML has been associated with response to immune checkpoint inhibition in paediatric gliomas, the identification of a subtype of ultra-mutated <i>IDH</i>-wt GBM may have implications for immunotherapy.
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