The Spatial Signature of Glioblastoma: A Statistical Re-Assessment of Anatomical Distribution Based on Methylation Subtypes.

Precise molecular characterization of glioblastoma (GB) is fundamental for accurate risk stratification and therapeutic planning. DNA methylation profiling reliably identifies key molecular features, including O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status and specific molecular subtypes, such as receptor tyrosine kinase (RTK) I and II, and the mesenchymal (MES) subtype. In this study, we investigated the hypothesized correlation between these molecular profiles and preferential tumor locations, which could reveal a link to underlying tumor biology. We analyzed 227 GB patients characterized by DNA methylation profiling. To map significant clusters of tumor occurrence across subtypes and subcomponents, we performed voxel-wise analysis of differential involvement, utilizing 500 permutations to correct for multiple comparisons. While uncorrected frequency differential maps suggested localization tendencies for the RTK I, RTK II, and MES subtypes, stringent statistical correction revealed only one robust association: the non-enhancing component of MES tumors showed significant clustering in the left frontal lobe, the insula, and the temporal lobe. Contrary to prior literature, we observed no significant hemispheric preference regarding MGMT promoter methylation status. Our findings challenge prior assumptions regarding the spatial distinctiveness of GB subtypes and highlight the need to further elucidate the mechanisms governing tumorigenesis and spatial growth patterns.