Given the potential for discovery of biomarkers and actionable targets leveraging the proteomic data, we set out to identify regional proteomic signatures with LC-MS/MS in diffuse gliomas samples selected based on histopathological criteria, aiming to achieve the following: (i) identify proteins and molecular pathways involved in glioma evolution; and (ii) validate the high mobility group protein B2 (HMGB2) as a key player in tumor progression and as a prognostic/predictive biomarker for diffuse astrocytomas. Here, HMGB2 is linked to central nervous system cancer.