Conclusions:

TMB-H is associated with POLE mutation, high rate of GC>TA transition and microsatellite instability. – GC>TA high, an indicator of alkylator-induced phenotype, is associated with MSI-H; and the concurrent GC>TA high and MSI-H further increase TMB. – MSI-H or TMB-H is not associated with increased PD-L1 expression. – Paired sample analysis confirms that temozolomide sensitivity markers including MGMT-Me and IDH mutations are more prevalent in tumors acquiring hypermutation phenotype. – Our results support the notion that unlike other cancer types, TMB-H in glioma may not associate with increased response to Immuno-Oncology therapy – Further understanding of molecular and immune profile of the TMB-H may facilitate more individualized treatment planning – A clinical trial of treating TMB-High glioma patients differentially according to the underlying molecular drivers is warranted.