O-6-methylguanine-DNA methyltransferase promoter methylation can change in glioblastoma recurrence due to intratumor heterogeneity

Abstract

Background and Aim: The standard-of-care for patients with glioblastoma (GBM) is surgery followed by concurrent chemotherapy with temozolomide and radiotherapy. O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation is commonly assessed in GBM as a predictive marker of response to temozolomide. Although MGMT methylation status has been shown to change between primary and recurrent GBM, no indication exists on retesting MGMT in recurrent GBM. In addition, what causes the change in MGMT methylation has yet to be identified. In this study, we aimed to investigate whether MGMT promoter methylation in recurrent GBM was influenced by intratumor heterogeneity in the initial GBM tumor. Materials and Methods: We investigated the status of MGMT promoter methylation in different samples taken from concentric layers of 24 GBMs and in 11-paired surgically resected recurrences. The neoplastic nature of samples submitted for methylation analysis was preliminary verified through histological examination; the fragments were accurately chosen to have adequate cellularity and minimal amount of nontumor contaminants. Results: About 27% (3 out of 11) of the recurrences had changed MGMT methylation status compared to the initial tumor. Initial tumor heterogeneity might play a role in this change, as all three cases had intratumor heterogeneity (with the central part of the tumor methylated and the peripheral part unmethylated) in the primary GBM. Conclusion: This study suggests that MGMT methylation variation in recurrent GBM may depend on intratumor heterogeneity in the initial tumor. Intratumor heterogeneity and possible changes in the recurrence should be taken into account when testing MGMT promoter methylation status as a predictive factor orienting therapeutic decisions in patients with GBM.