Intratumoral preservation of the stem-like malignant cell proportion in glioblastoma, prognostic impact, and its radiomethylomic signatures

Abstract

Background. Glioblastoma (GBM) exhibits significant intratumoral heterogeneity. However, the presence andextent of intratumoral heterogeneity of stem-like and differentiated cell components based on methylation profiles remain poorly understood. Furthermore, the utility of integrating methylation profiles with radiomic features(radiomethylomics) for predicting these cellular states has not been explored.Methods. We analyzed 248 samples from 133 GBM patients, including 157 samples from 42 patients whose tumors were sampled at multiple points. Two distinct methylation-based deconvolution analyses were performed toassess cellular composition. Radiomethylomic models were developed using support vector machines with features extracted from multi-parametric MRI.Results. Multi-sampling analysis revealed that the proportion of stem-like cells among total malignant cells washomogeneously preserved within tumors. Tumors harboring a higher proportion of stem-like cells (stem-liketumors) showed significantly shorter overall survival and diminished benefits from O6-methylguanine DNAmethyltransferase (MGMT) promoter methylation. Stem-like tumors showed a strong correlation with the RTK Isubtype. Integrating physiological MRI features (diffusion tensor imaging and dynamic susceptibility contrast) withconventional sequences enhanced the performance of radiomethylomic models for predicting stem-like tumorstatus and prognostic stratification.Conclusions. Our findings reveal a homogeneous preservation of the proportion of stem-like cells over total malignant cells within GBM, establishing its significance as a tumor-wide feature. The development of radiomethylomicsignatures shows potential for noninvasive assessment of tumor stemness, ultimately facilitating personalizedtreatment strategies in light of the prognostic impact of the feature.