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.

Widely metastatic glioblastoma with BRCA1 and ARID1A mutations: a case report

“…Possible mechanisms include acquired inactivating mutations or epigenetic silencing of the MMR genes MSH6, MSH2, MLH1, and PMS2. Recent studies show that treatment with TMZ of MGMT unmethylated tumors, such as in our case, introduces a strong selective pressure to lose mismatch repair pathway function [26]. Although immunostaining demonstrated intact MMR protein expression in the recurrent and metastatic specimens of our case, mutational hotspot analysis of the PDX derived from the temporal recurrence revealed inactivation of ARID1A, which has recently been shown to promote MMR by interacting with MSH2 [27].…”

Studies for Better Treatment of Patients with Glioma

“…Preliminary results have failed to show an advantage of nivolumab for GBM 114 . One explanation could be the relatively low mutational burden in GBM as compared to many other malignancies 115 . In an interesting paper by Costello et al, they discuss the effects of TMZ to cause a "hypermutated phenotype" in tumor recurrences.…”

“…In an interesting paper by Costello et al, they discuss the effects of TMZ to cause a "hypermutated phenotype" in tumor recurrences. This occurs when the tumor is MGMT methylated and lacks intact MMR genes 104,115 . They hypothesize that this hypermutated tumor cell might be a functional target for immune therapy, as the mutational burden has been correlated to efficacy 115 .…”

“…This occurs when the tumor is MGMT methylated and lacks intact MMR genes 104,115 . They hypothesize that this hypermutated tumor cell might be a functional target for immune therapy, as the mutational burden has been correlated to efficacy 115 . Another monoclonal antibody against PD-1, pembrolizumab, is currently being investigated for recurrent gliomas with hypermutator phenotype (NCT02658279) 115 .…”

Immunotherapy in Glioblastoma: Current Shortcomings and Future Perspectives

“…However, no tumor responses were observed in four other patients with hypermutated recurrent glioblastomas treated with ICIs [13]. TMZ treatment can also result in tumors with a high mutational load due to acquired mutations in the DNA repair genes MSH2, MSH6, PMS2, and MLH2 [14][15][16][17], and these tumors are likely more immunogenic compared to other glioblastomas. Hypermutation at glioblastoma diagnosis or at recurrence is associated with enhanced numbers of CD8 T cells [18].…”