MGMT gene promoter methylation by pyrosequencing method correlates volumetric response and neurological status in IDH wild-type glioblastomas

Abstract

Purpose Although the usefulness of O6-methylguanine DNA methyltransferase (MGMT) promoter methylation analysis for predicting response to chemoradiotherapy and the prognosis of patients with glioblastoma has been widely reported, there is still no consensus regarding how to define MGMT promoter methylation percentage (MGMTpm%) cutoffs by pyrosequencing method. The aim of this study was to determine the optimal cutoff value of MGMT promoter methylation status using volumetric analysis focused on the tumor volume ratio (TVR) measured by MRI. Methods This retrospective study included newly diagnosed IDH wild-type glioblastoma patients with residual tumor after surgery, followed by local radiotherapy with temozolomide. TVR was defined as the tumor volume at 6 months after the initial chemoradiotherapy administration divided by the tumor volume before the start of therapy. The mean MGMTpm% of 16 CpG islands (74–89) was analyzed using pyrosequencing. We statistically analyzed the correlation between MGMTpm%, TVR, and change in Karnofsky performance status. Results The study included 44 patients with residual tumors. Thirteen (92.9%) of 14 patients with MGMTpm% ≥ 23.9% showed 50% or more volumetric response, leading to prolonged survival, and 17 (70.8%) of 24 patients with MGMTpm% < 8.2% had progressive disease after initial chemoradiotherapy administration. Three (50.0%) of six patients with MGMTpm% 8.2% to < 23.9% had stable disease or partial response. Conclusion Evaluation of MGMTpm% by pyrosequencing is important in predicting the volumetric response and prognosis of glioblastoma patients with residual tumors.

Volumetric Analysis of Glioblastoma for Determining Which CpG Sites Should Be Tested by Pyrosequencing to Predict Temozolomide Efficacy

“…Non-contrast-enhanced areas within the contrast-enhanced areas were measured as lesions, but obvious cystic lesions or postoperative extraction cavities were excluded. TVR was defined as the tumor volume 6 months after the initial chemoradiotherapy divided by that before the start of chemoradiotherapy [ 9 ].…”

“…MGMT promoter methylation percentage ( MGMT pm%) obtained with pyrosequencing correlates with the tumor volume ratio (TVR) obtained with magnetic resonance imaging (MRI) in isocitrate dehydrogenase (IDH)-wildtype glioblastoma [ 9 ]. The aim of the present study was to determine which individual or combined CpGs mainly affect the response to chemotherapy resulting from MGMT CpG methylation using statistical analyses focused on TVR.…”

Pyrosequencing Analysis of O-6-Methylguanine-DNA Methyltransferase Methylation at Different Cut-Offs of Positivity Associated with Treatment Response and Disease-Specific Survival in Isocitrate Dehydrogenase-Wildtype Grade 4 Glioblastoma

“…In GBMs, the absence of MGMT methylation, known as MGMT promoter unmethylation, often translates into a more challenging clinical scenario, tending to present resistance to chemotherapy. The same occurs in astrocytomas, in which MGMT promoter methylation generally means a more favorable prognosis [ 17 , 18 , 19 ].…”

“…This epigenetic silencing of the MGMT gene increases the sensitivity of tumor cells to alkylating chemotherapeutic agents, leading to better treatment responses and potentially prolonged survival [ 18 , 19 ]. The intricate interplay between MGMT methylation status and prognosis underscores the critical role of epigenetics in defining the course of these aggressive CNS tumors, ultimately guiding therapeutic decisions and offering hope to both patients and clinicians [ 3 , 16 , 20 , 21 , 22 , 23 , 24 , 25 ].…”

‘The Reports of My Death Are Greatly Exaggerated’—Evaluating the Effect of Necrosis on MGMT Promoter Methylation Testing in High-Grade Glioma

“…Pyrosequencing gives a quantitative picture of individual CpG sites within MGMT [27,28,31], as well as being a relatively cheap assay that is amenable to application in a high throughput setting. MGMT promoter methy-lation analysis by pyrosequencing has been repeatedly shown to be the most sensitive method for clinical use [27,28,31] and a robust prognostication tool [27,28,[31][32][33][34][35][36].…”