Glioma are the most common type of malignant
brain tumor, with
glioblastoma (GBM) representing the most common and most lethal type of
glioma. Surgical resection followed by
radiotherapy and
chemotherapy using the
alkylating agent Temozolomide (TMZ) remain the mainstay of treatment for
glioma. While this multimodal regimen is sufficient to temporarily eliminate the bulk of the
tumor mass, recurrence is inevitable and often poses major challenges for clinical management due to treatment resistance and failure to respond to targeted
therapies. Improved
tumor profiling capacity has enabled characterization of the genomic landscape of
gliomas with the overarching goal to identify clinically relevant subtypes and inform treatment decisions. Increased
tumor mutational load has been shown to correlate with higher levels of neoantigens and is indicative of the potential to induce a durable response to
immunotherapy. Following treatment with TMZ, a subset of
glioma has been identified to recur with increased
tumor mutational load. These hypermutant recurrent
glioma represent a subtype of recurrence with unique molecular vulnerabilities. In this review, we will elaborate on the current knowledge regarding the evolution of hypermutation in
gliomas and the potential therapeutic opportunities that arise with TMZ-induced hypermutation in
gliomas.