“Hyper-Hypermethylated Status” of the MGMT Gene Promoter Confers Additional Survival Benefits in IDH-Wild-Type Glioblastoma Patients

Abstract IntroductionMethylation status of the O(6)-Methylguanine-DNA methyltransferase (MGMT) promoter plays key role in glioblastoma (GBM) with respect to the patient’s responses to temozolomide chemotherapy and disease prognosis. Although the cut-off value of MGMT methylation (≥10%) is currently widely used to dichotomize the MGMT status as “methylated” or “unmethylated” in pyrosequencing (PSQ) analysis, it is still unclear whether it reflects the actual MGMT methylation status of the patients. Thus, we investigated if there is a so called “hyper-hypermethylation cut-off value” that confers additional survival benefits in IDH-wild-type GBM patients. MethodsWe retrospectively analyzed a cohort of 110 isocitrate dehydrogenase (IDH)-wild-type GBM patients who underwent gross total resection followed by the standard treatment. Predictive “hyper-hypermethylated” cutoff values that yielded maximal differences in survival were investigated. ResultsThe estimated hyper-hypermethylated cutoff value was 40%. The median OS values for unmethylated, low-methylated, and hyper-hypermethylated groups were 16, 17, and 23 months, respectively. With regard to disease progression, the median progression-free survival (PFS) values were 11, 14, and 16 months, respectively. The hyper-hypermethylated MGMT cutoff values were correlated with significantly improved overall survival (OS), compared to the low-methylated (p=0.039, HR=3.86, CI=1.1 to 13.8) or unmethylated groups (p=0.023, HR=3.92, CI=1.21 to 12.6). ConclusionThus, in addition to the standard MGMT cut-off point of 10%, we suggest that a so-called “hyper-hypermethylated” MGMT cut-off point may confer additional survival benefits in IDH-wild-type GBM patients.