The Clinical Significance of O6-Methylguanine-DNA Methyltransferase Promoter Methylation Status in Adult Patients With Glioblastoma: A Meta-analysis

Abstract

Background and objectivePromoter status of O6-methylguanine-DNA methyltransferase (MGMT) has been widely established as a clinically relevant factor in glioblastoma (GBM) patients. However, in addition to varied therapy schedule, the prognosis of GBM patients is also affected by variations of age, race, primary or recurrent tumor. This study comprehensively investigated the association between MGMT promoter status and prognosis in overall GBM patients and in different GBM subtype including new diagnosed patients, recurrent patients and elderly patients.MethodsA comprehensive search was performed using PubMed, EMBASE, Cochrane databases to identify literatures (published from January 1, 2005 to April 1, 2017) that evaluated the associations between MGMT promoter methylation and prognosis of GBM patients.ResultsTotally, 66 studies including 7,886 patients met the inclusion criteria. Overall GBM patients with a methylated status of MGMT receiving temozolomide (TMZ)-containing treatment had better overall survival (OS) and progression-free survival (PFS) [OS: hazard ratio (HR) = 0.46, 95% confidence interval (CI): 0.41–0.52, p < 0.001, Bon = 0.017; PFS: HR = 0.48, 95% CI 0.40–0.57, p < 0.001, Bon = 0.014], but no significant advantage on OS or PFS in GBM patients with TMZ-free treatment was observed (OS: HR = 0.97, 95% CI 0.91–1.03, p = 0.08, Bon = 1; PFS: HR = 0.76, 95% CI 0.57–1.02, p = 0.068, Bon = 0.748). These different impacts of MGMT status on OS were similar in newly diagnosed GBM patients, elderly GBM patients and recurrent GBM. Among patients receiving TMZ-free treatment, survival benefit in Asian patients was not observed anymore after Bonferroni correction (Asian OS: HR = 0.78, 95% CI 0.64–0.95, p = 0.02, Bon = 0.24, I2 = 0%; PFS: HR = 0.69, 95% CI 0.50–0.94, p = 0.02, Bon = 0.24). No benefit was observed in Caucasian receiving TMZ-free therapy regardless of Bonferroni adjustment.ConclusionThe meta-analysis highlights the universal predictive value of MGMT methylation in newly diagnosed GBM patients, elderly GBM patients and recurrent GBM patients. For elderly methylated GBM patients, TMZ alone therapy might be a more suitable option than radiotherapy alone therapy. Future clinical trials should be designed in order to optimize therapeutics in different GBM subpopulation.

OKN-007 Increases temozolomide (TMZ) Sensitivity and Suppresses TMZ-Resistant Glioblastoma (GBM) Tumor Growth

“…From previous studies, it is well known that O 6 -methylguanine-DNA methyltransferase (MGMT) [9] , N -methylpurine DNA glycosylase (MPG; also known as alkylpurine-DNA- N -glycosylase or APNG) [10] , and hypoxia inducible factor 1α (HIF-1α) [11] are all associated with TMZ-resistance in GBM. Drug resistance against TMZ is mediated by increasing MGMT levels [2] .…”

Methylation of MGMT promoter does not predict response to temozolomide in patients with glioblastoma in Donostia Hospital

“…The patients with GBM who benefit most from TMZ are those who do not have MGMT 26 . Nonetheless, in our cohort, MGMT promoter methylation did not affect TMZ-mediated survival.…”

“…For example, the transcription and subsequent expression of the MGMT protein may be affected by genetic factors such as single nucleotide polymorphisms (SNPs) in the gene promoter region. Genome-wide association studies have identified some SNPs that increase the risk of developing GBM 26 , 29 . Among these, the MGMT promoter SNP rs16906252 seems to play a key role in the acquisition of MGMT methylation, and hence, increases the risk of developing MGMT-methylated GBM 29 .…”

Distinct DNA Methylation Profiles in Ovarian Tumors: Opportunities for Novel Biomarkers

“…Our data on survival analyses showed that MGMT hypermethylation leads to a higher survival rate. This could be due to its role in DNA repair and thus, a better response to chemotherapy, as observed in glioblastoma [ 45 ] but also in advanced ovarian cancer [ 46 ]. In our cases, the link between hypermethylation and better survival was found particularly for serous and mucinous histotypes.…”