Diagnostic, prognostic and predictive significance of the immunohistochemical loss of H3K27me3 in different CNS and extra-CNS tumors

Epigenetic regulation is essential for normal development, influencing critical biological processes such as cell differentiation, tissue development, and responses to environmental factors. The epigenetic signature in cells is a dynamic process changing over time and adapting to internal and environmental stimuli. Dysregulation of these processes is associated with various diseases, including inflammatory and degenerative conditions, as well as cancers. Indeed, several epigenetic changes have been implicated in cancer onset, progression, and in modulating the effectiveness of treatments, and the ongoing research in this field holds promise for developing novel therapeutic strategies targeting epigenetic mechanisms. In recent years, among epigenetic modifications, dysregulation of the methylation status of the lysin at position 28 of Histone 3 (H3K27) has gained significant attention and loss of trimethylation of H3K27 (H3K27me3) has been extensively studied in various tumor types, in some of which it serves as a diagnostic and/or prognostic marker. In this project we aimed to investigate the diagnostic, prognostic and predictive role of H3K27me3 immunohistochemical loss in different central nervous system (CNS) and extra-CNS tumors. In diffuse intracranial gliomas, H3K27me3 loss was significantly correlated with the presence of 1p/19q codeletion and ATRX immunohistochemical retention, serving as a diagnostic marker in the differential diagnosis of IDH-mutant gliomas. In these tumors, H3K27me3 loss was also a prognostic marker, its loss being correlated with longer progression-free survival (PFS), independently of IDH1/2 mutations. We demonstrated H3 K27me3 loss in rosette forming glioneuronal tumors (RGNTs), without any correlation with clinical outcome. In intracranial meningiomas and rectal adenocarcinomas, H3 K27me3 loss was significantly associated with shorter PFS after radiotherapy, suggesting that this staining could be used as a predictive biomarker in these tumors. Therefore, our data demonstrate that H3K27me3 loss has a different and opposite prognostic significance in different tumor types. Despite the diagnostic, prognostic and predictive value of H3 K27me3 loss in human tumors, a standardized protocol for its assessment and interpretation is urgently needed for its use in routine practice.