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. 2022 May 13;14(10):2425.
doi: 10.3390/cancers14102425.

Definition of the Prognostic Role of MGMT Promoter Methylation Value by Pyrosequencing in Newly Diagnosed IDH Wild-Type Glioblastoma Patients Treated with Radiochemotherapy: A Large Multicenter Study

Mario Caccese  1 , Matteo Simonelli  2   3 , Veronica Villani  4 , Simona Rizzato  5 , Tamara Ius  6 , Francesco Pasqualetti  7   8 , Marco Russo  9 , Roberta Rudà  10   11 , Rosina Amoroso  12 , Luisa Bellu  13 , Roberta Bertorelle  14 , Francesco Cavallin  15 , Angelo Dipasquale  2   3 , Mariantonia Carosi  16 , Stefano Pizzolitto  17 , Daniela Cesselli  18   19 , Pasquale Persico  2   3 , Beatrice Casini  16 , Matteo Fassan  20   21 , Vittorina Zagonel  1 , Giuseppe Lombardi  1
Affiliations

Definition of the Prognostic Role of MGMT Promoter Methylation Value by Pyrosequencing in Newly Diagnosed IDH Wild-Type Glioblastoma Patients Treated with Radiochemotherapy: A Large Multicenter Study

Mario Caccese et al. Cancers (Basel). .

Abstract

Background. O6-methylguanine (O6-MeG)-DNA methyltransferase (MGMT) methylation status is a predictive factor for alkylating treatment efficacy in glioblastoma patients, but its prognostic role is still unclear. We performed a large, multicenter study to evaluate the association between MGMT methylation value and survival. Methods. We evaluated glioblastoma patients with an assessment of MGMT methylation status by pyrosequencing from nine Italian centers. The inclusion criteria were histological diagnosis of IDH wild-type glioblastoma, Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ≤2, and radio-chemotherapy treatment with temozolomide. The relationship between OS and MGMT was investigated with a time-dependent Receiver Operating Characteristics (ROC) curve and Cox regression models. Results. In total, 591 newly diagnosed glioblastoma patients were analyzed. The median OS was 16.2 months. The ROC analysis suggested a cut-off of 15% for MGMT methylation. The 2-year Overall Survival (OS) was 18.3% and 51.8% for MGMT methylation <15% and ≥15% (p < 0.0001). In the multivariable analysis, MGMT methylation <15% was associated with impaired survival (p < 0.00001). However, we also found a non-linear association between MGMT methylation and OS (p = 0.002): median OS was 14.8 months for MGMT in 0−4%, 18.9 months for MGMT in 4−40%, and 29.9 months for MGMT in 40−100%. Conclusions. Our findings suggested a non-linear relationship between OS and MGMT promoter methylation, which implies a varying magnitude of prognostic effect across values of MGMT promoter methylation by pyrosequencing in newly diagnosed IDH wild-type glioblastoma patients treated with chemoradiotherapy.

Keywords: MGMT; glioblastoma; methylation; pyrosequencing; temozolomide.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Flow diagram of patient selection.
Figure 2
Figure 2
Overall survival of glioblastoma patients with assessment of MGMT promoter methylation status by PSQ approach.
Figure 3
Figure 3
Receiver operating characteristics (ROC) curve of MGMT promoter methylation for 2-year overall survival (OS) in glioblastoma patients (A); overall survival for patients with MGMT methylation ≥15% and those with MGMT <15%, according to the cut-off suggested by ROC curve analysis (B).
Figure 4
Figure 4
Hazard ratio according to MGMT promoter methylation under the assumption of linear association (A) or non-linear association (B); median survival according to MGMT promoter methylation under the assumption of linear association (C) or non-linear association (D).
See this image and copyright information in PMC

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