MGMT Promoter and Enhancer Methylation in Melanoma Brain Metastases and Glioblastoma: Shared and Distinct Features

Many cancer-associated deaths result from metastases rather than primary tumors. Growing evidence suggests that DNA methylation alterations are crucial for inducing a plastic phenotype that allows cancer cells to adapt to the metastatic microenvironment. Brain metastases of melanoma (MBM) and glioblastoma (GB) share a neuroectodermal origin and the brain as tissue of residence, but their epigenetic regulation is poorly understood. Aiming at elucidating shared and tumor-distinct features, we analyzed the methylation of <i>MGMT</i> regulatory elements. We focused on <i>MGMT</i> because <i>MGMT</i> promoter methylation is used as a predictive marker for temozolomide response in GB, but its role in MBM has been discussed controversially. By targeting 12 CpG dinucleotides (CpGs) in the promoter, 68 CpGs in intergenic enhancers, and 31 CpGs in intragenic enhancers, we identified shared features, including an L-shaped relationship between promoter methylation and MGMT protein expression and an inverse L-shaped relationship between intragenic enhancer methylation and MGMT protein expression. GB exhibited higher methylation, particularly in promoter and intergenic enhancers, and stronger associations between methylation and overall survival than MBM. These results highlight both conserved and tumor-specific <i>MGMT</i> regulation, reflecting the complexity of epigenetic control in brain malignancies and emphasizing divergent evolution between MBM and GB.