A novel MGMT methylation-based prognostic score in patients with glioblastoma.

Background: The methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter has been associated with improved outcome in glioblastoma (GBM) patients (pts). Pyrosequencing (PSQ) has been reported to be an accurate method for quantitative detection of CpG islands (CpGs) methylation, but the role of methylation heterogeneity among different CpGs sites is still unclear. Aim of this study was to evaluate on a large multicentric cohort a novel prognostic score based on the evaluation of the MGMT promoter methylation at 10 different CpGs sites.

Methods: We retrospectively analyzed a series of 185 pts with GBM treated at the University Hospital of Udine and Istituto Oncologico Veneto in Padua between 2006 and 2015. The methylation level of 10 CpGs (74 – 83) was determined by PSQ. The cut-off point of 9% was used to define a CpG as methylated. One point was assigned to each methylated CpG, with a total score from 0 (all CpGs < 9%) to 10 (all CpGs ≥ 9%). A threshold capable to detect a favorable outcome (Overall Survival, OS > 24 months) has been identified through ROC analysis as 6 by a previous study conducted at our center. The prognostic impact was explored through Cox regression.

Results: After a median follow-up of 59 months, the median OS and Progression Free Survival (PFS) in the whole population were 16.41 and 9.67 months, respectively. A score ≥ 6 identified pts with a considerably better median OS (24.85 vs 12.99 months, p < .0001) and PFS (11.44 vs 8.22 months, p < .0001). On multivariate analysis, it remained independently associated with a favorable prognosis (HR 0.38, 95% CI 0.27-0.55, p < 0.0001) after adjustment for IDH1 mutational status (HR 0.42, 95% CI 0.20-0.87, p = .02), age ( > 70 vs ≤ 70 years HR 2.20, 95% CI 1.48-3.28, p = .0001) and ECOG performance status (2-3 vs 0-1 HR 2.35, 95% CI 1.59-3.49, p < .0001). The score’s prognostic value was maintained in all the explored subgroups.

Conclusions: Combining methylation data from multiple CpGs increases the prognostic value of the MGMT promoter methylation assessment. The study confirmed the independent prognostic value of a novel score system based on the evaluation of the MGMT promoter methylation at 10 different CpGi sites.

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