IDH mutation and MGMT promoter methylation in glioblastoma: results of a prospective registry

Abstract

BackgroundThe relative contribution of isocitrate dehydrogenase mutations (mIDH) and O6-methylguanine-DNA methyltransferase promoter methylation (methMGMT) as biomarkers in glioblastoma remain poorly understood.MethodsWe investigated the association between methMGMT and mIDH with progression free survival and overall survival in a prospectively collected molecular registry of 274 glioblastoma patients.ResultsFor glioblastoma patients who underwent Temozolomide and Radiation Therapy, OS and PFS was most favorable for those with tumors harboring both mIDH and methMGMT (median OS: 35.8 mo, median PFS: 27.5 mo); patients afflicted glioblastomas with either mIDH or methMGMT exhibited intermediate OS and PFS (mOS: 36 and 17.1 mo; mPFS: 12.2 mo and 9.9 mo, respectively); poorest OS and PFS was observed in wild type IDH1 (wtIDH1) glioblastomas that were MGMT promoter unmethylated (mOS: 15 mo, mPFS: 9.7 mo). For patients with wtIDH glioblastomas, TMZ+RT was associated with improved OS and PFS relative to patients treated with RT (OS: 15.4 mo v 9.6 mo, p < 0.001; PFS: 9.9 mo v 6.5 mo, p < 0.001). While TMZ+RT and RT treated mIDH patients exhibited improved overall survival relative to those with wtIDH, there were no differences between the TMZ+RT or RT group. These results suggest that mIDH1 conferred resistance to TMZ. Supporting this hypothesis, exogenous expression of mIDH1 in independent astrocytoma/glioblastoma lines resulted in a 3–10 fold increase in TMZ resistance after long-term passage.ConclusionOur study demonstrates IDH mutation and MGMT promoter methylation status independently associate with favorable outcome in TMZ+RT treated glioblastoma patients. However, these biomarkers differentially impact clinical TMZ response.

Potential Role of Methylation Marker in Glioma Supporting Clinical Decisions

“…In an important report by Yang et al, a role of the mutated IDH1 gene in the resistance to temozolomide therapy is suggested. The article confirms the hypothesis in astrocytoma/glioblastoma cell lines, in which exogenous expression of the mutated IDH1 results in a three- to 10-fold increase in temozolomide resistance after long-term passage [18]. Unfortunately, our group of seven patients who received Temozolomide (TMZ) was too small for similar conclusions or any statistical evaluation (only three patients were diagnosed with astrocytoma II and 4 with GBM, and received chemotherapy; all of them, excluding one, had the mutation in IDH1 and the methylated MGMT ; data not shown).…”

“…The IDH1 /2 mutations, 1p/19q status and MGMT promoter methylation are commonly recognized biomarkers in patients with gliomas [16,17,18]. Their role as prognostic or predictive biomarkers—that can be used in diagnostics—is growing.…”

“…It was demonstrated that in malignant gliomas of WHO grades III/IV with the IDH1 mutation, MGMT promoter methylation was associated with prolonged Progression-free survival (PFS) with chemotherapy ± radiation therapy (RT) or RT-only groups [19]. Moreover, a recent investigation (in which a molecular registry of 274 glioblastoma patients was used) showed that the poorest OS and PFS were observed in wild-type IDH1 glioblastomas with an unmethylated MGMT promoter [18]. Our results are in concordance with the above results: the best OS was observed in all patients, regardless of their histopathological type, who had hypermethylated MGMT and mutated IDH1 , with a median of 33.5 months ( n = 30).…”

Heat shock protein peptide complex-96 vaccination for newly diagnosed glioblastoma: a phase I, single-arm trial

“…Median PFS and OS were 8.1 months and 16.0 months, respectively, in the TCGA cohort. Pei Yang et al (24) have reported outcomes in a cohort of 274 GBM patients from our center. In Yang's cohort, PFS was 71% at 6 months and median PFS and OS were 10.7 and 17.8 months, respectively, among 229 patients who received Stupp's regimen.…”

Isocitrate dehydrogenase 1 and 2 genes mutations and MGMT methylation in gliomas

“…Обнаруженная частичная ассоциация между метилированием MGMT и мутация-ми IDH1 / 2 указывает на необходимость анализа статуса обоих маркеров для ведения больных после удаления глиом. Определение 2 маркеров тем более важно, по-скольку каждый из них имеет независимую ассоциацию с повышенной выживаемостью пациентов, подверга-ющихся радиотерапии в сочетании с алкилирующими агентами, и, по-видимому, различным образом влияет на клинический ответ на терапию [29,30].…”