Potential Role of Methylation Marker in Glioma Supporting Clinical Decisions

Abstract

The IDH1/2 gene mutations, ATRX loss/mutation, 1p/19q status, and MGMT promoter methylation are increasingly used as prognostic or predictive biomarkers of gliomas. However, the effect of their combination on radiation therapy outcome is discussable. Previously, we demonstrated that the IDH1 c.G395A; p.R132H mutation was associated with longer survival in grade II astrocytoma and GBM (Glioblastoma). Here we analyzed the MGMT promoter methylation status in patients with a known mutation status in codon 132 of IDH1, followed by clinical and genetic data analysis based on the two statuses. After a subtotal tumor resection, the patients were treated using IMRT (Intensity-Modulated Radiation Therapy) with 6 MeV photons. The total dose was: 54 Gy for astrocytoma II, 60 Gy for astrocytoma III, 60 Gy for glioblastoma, 2 Gy per day, with 24 h intervals, five days per week. The patients with MGMT promoter methylation and IDH1 somatic mutation (OS = 40 months) had a better prognosis than those with MGMT methylation alone (OS = 18 months). In patients with astrocytoma anaplasticum (n = 7) with the IDH1 p.R132H mutation and hypermethylated MGMT, the prognosis was particularly favorable (median OS = 47 months). In patients with astrocytoma II meeting the above criteria, the prognosis was also better than in those not meeting those criteria. The IDH1 mutation appears more relevant for the prognosis than MGMT methylation. The IDH1 p.R132H mutation combined with MGMT hypermethylation seems to be the most advantageous for treatment success. Patients not meeting those criteria may require more aggressive treatments.

Prognostic and Predictive Biomarkers in Gliomas

“…A combination of both IDH mutations and MGMT promoter methylation was associated with the best response rates to TMZ [ 33 , 36 ]. Moreover, Roszkowski et al found that patients with both MGMT promoter methylation and IDH1 mutations receiving radiotherapy had a better prognosis than those with MGMT methylation alone [ 150 ]. However, Vuong et al reported that not all GBM patients with methylated MGMT may benefit from TMZ, postulating that it is possible that only GBM patients mutated by TERT with MGMT methylation are sensitive [ 59 ].…”

Elevated CD44 expression predicts poor prognosis in patients with low‑grade glioma

“…Although traditional histopathological methods are regarded as the gold standard for LGG classification, they do not adequately predict clinical outcome. Consequently, an increasing number of studies have shown that biomarkers may improve the clinical decision-making process (5). Hypermethylation of the O 6 -methylguanine-DNA methyltransferase promoter can effectively predict the responsiveness to temozolomide (6).…”

Differential gene methylation patterns in cancerous and non‑cancerous cells

“…Therefore, unique expression and methylation patterns have been introduced in diagnostics as prognostic and predictive biomarkers. Since the best-known expression profiling performed 15 years ago in breast cancer (41), determination of the unique signature of gene expression (6,42) or promoter methylation is used more frequently, for example MGMT methylation in tumor tissue as a biomarker in glioma (43) or SEPT9 methylation in plasma as a biomarker in colorectal adenocarcinoma (44).…”

“…MGMT is an important glioblastoma prognostic and predictive biomarker in clinical use (43). Reports regarding prostate cancer are inconclusive (46,56,61).…”