Histone H3 variants are associated with distinctive glioma entities

Gliomas constitute a heterogeneous group of primary brain cancers, being glioblastoma (GBM) the most prevalent and aggressive form. Despite intensive research, current biomarkers and therapies are still not applied in a personalized manner, and do not prevent recurrency. H3.3 is a non-canonical, replication-independent histone H3 variant which alterations have gain- and loss-of-function effects in pediatric and adult GBM, respectively. The canonical replication-dependent H3.1/H3.2 variants remain largely unexplored in gliomas. We examined these variants in surgical resections of two independent adult cohorts by combining immunodetection and gene expression assays (Western blotting, immuhistochemistry, RT-qPCR, RNA-seq).H3.3 was more associated with low-grade, better outcome gliomas whereas H3.1/H3.2 were more associated with high-grade, lower outcome gliomas. The latter variants produced a positive-or-negative staining pattern that is more plausible to be implemented in the diagnosis pipeline of Anatomical Pathology departments. Due to the high variability observed in GBM, we investigated whether tumours with different levels of H3.1/H3.2 showed different properties of potential clinical relevance. Analysis in both fresh-frozen and FFPE samples revealed that GBM expressing high levels of canonical histone variants were more linked to mitosis and proliferation, but not with tumoural microenvironment parameters such as infiltration of immune cells. Detection of H3.1/H3.2 was confirmed to be positively correlated with proliferative index (% Ki67+ cells). Further research is required to understand the genomic roles of the H3.1, H3.2 and H3.3 in gliomagenesis and their behaviour in epigenetic-based therapies.This research is financed by INNEST/2022/168 (AVI-FEDER) and 2022-0320 (ISABIAL).