Relationship between glioblastoma location and O⁶-methylguanine-DNA methyltransferase promoter methylation percentage

A large literature assessed the relationships between the O⁶-methylguanine-DNA methyltransferase (MGMT) promoter methylation status and glioblastoma location with inconsistent results. Studies assessing this association using the percentage of methylation are lacking. This cross-sectional study aimed at investigating relationships between glioblastoma topology and MGMT promoter methylation, both as categorical (presence/absence) and continuous (percentage) status. We included patients with diagnosis of isocitrate dehydrogenase wild-type glioblastoma [World Health Organization (WHO) 2021 classification], available pre-surgical MRI, known MGMT promoter methylation status. Quantitative methylation assessment was obtained through pyrosequencing. Several analyses were performed for categorical and continuous variables (χ ², t-tests, ANOVA and Pearson's correlations), investigating relationships between MGMT methylation and glioblastoma location in cortex/white matter/deep grey matter nuclei, lobes, left/right hemispheres and functional grey and white matter network templates. Furthermore, we assessed at the voxel-wise level location differences between (i) methylated and unmethylated glioblastomas and (ii) highly and lowly methylated glioblastomas. Lastly, we investigated the linear relationship between glioblastoma-voxel location and the MGMT methylation percentage. Ninety-three patients were included (66 males; mean age: 62.3 ± 11.3 years), and 42 were MGMT methylated. The mean methylation level was 33.9 ± 18.3%. No differences in glioblastoma volume and location were found between MGMT-methylated and MGMT-unmethylated patients. No specific anatomical regions were associated with MGMT methylation at the voxel-wise level. MGMT methylation percentage positively correlated with cortical localization (R = 0.36, P = 0.021) and negatively with deep grey matter nuclei localization (R = -0.35, P = 0.025). To summarize, we investigated relationships between MGMT methylation status and glioblastoma location through multiple approaches, including voxel-wise analyses. In conclusion, MGMT promoter methylation percentage positively correlated with cortical glioblastoma location, while no specific anatomical regions were associated with MGMT methylation status.