Temozolomide-associated hypermutation in gliomas

Abstract

Low-grade gliomas cause considerable morbidity and most will recur after initial therapy. At recurrence, low-grade gliomas can undergo transformation to high-grade gliomas (grade III or grade IV), which are associated with worse prognosis. Temozolomide (TMZ) provides survival benefit in patients with glioblastomas, but its value in patients with low-grade gliomas is less clear. A subset of TMZ-treated, isocitrate dehydrogenase‒mutant, low-grade astrocytomas recur as more malignant tumors with thousands of de novo, coding mutations bearing a signature of TMZ-induced hypermutation. Preliminary studies raise the hypothesis that TMZ-induced hypermutation may contribute to malignant transformation, although with highly variable latency. On the other hand, hypermutated gliomas have radically altered genomes that present new opportunities for therapeutic intervention. In light of these findings and the immunotherapy clinical trials they inspired, how do patients and providers approach the risks and benefits of TMZ therapy? This review discusses what is known about the mechanisms and consequences of TMZ-induced hypermutation and outstanding questions regarding its clinical significance.

Fig. 1

Model of TMZ-associated malignant transformation. An initial low-grade glioma (A) is resected and residual disease is treated with TMZ, causing tumor cell death (B). If DNA repair capacity is low and TMZ-associated mutations occur within key amino acids of MMR genes, the loss of MMR function may render cells resistant to TMZ. Resistant cells can acquire high numbers of de novo TMZ-associated mutations, including thousands in coding regions, resulting in hypermutation (C). After widely varying periods of dormancy, clonal expansions of hypermutated cells drive formation of higher-grade tumor recurrences. Multiple unique hypermutated tumor clones may expand concurrently, as depicted by the different colored groups of hypermutated cells (D).