Potential Diagnostic Value of the Differential Expression of Histone H3 Variants between Low- and High-Grade Gliomas

Abstract

Glioblastoma (GB) is the most aggressive form of glioma and is characterized by poor prognosis and high recurrence despite intensive clinical interventions. To retrieve the key factors underlying the high malignancy of GB with potential diagnosis utility, we combined the analysis of The Cancer Gene Atlas and the REMBRANDT datasets plus a molecular examination of our own collection of surgical tumor resections. We determined a net reduction in the levels of the non-canonical histone H3 variant H3.3 in GB compared to lower-grade astrocytomas and oligodendrogliomas with a concomitant increase in the levels of the canonical histone H3 variants H3.1/H3.2. This increase can be potentially useful in the clinical diagnosis of high-grade gliomas, as evidenced by an immunohistochemistry screening of our cohort and can be at least partially explained by the induction of multiple histone genes encoding these canonical forms. Moreover, GBs showing low bulk levels of the H3.1/H3.2 proteins were more transcriptionally similar to low-grade gliomas than GBs showing high levels of H3.1/H3.2. In conclusion, this study identifies an imbalanced ratio between the H3 variants associated with glioma malignancy and molecular patterns relevant to the biology of gliomas, and proposes the examination of the H3.3 and H3.1/H3.2 levels to further refine diagnosis of low- and high-grade gliomas in future studies.

Diffuse Isocitrate Dehydrogenase–Mutant Gliomas With Histone H3 Alterations Are Distinguished by Unique Clinical Characteristics, Molecular Expression Profile, and Survival Prognosis

“…19 Consequently, many studies have reported the genomic landscape of specific H3-alterations in gliomas and their relationship with clinical characteristics and prognosis. [20][21][22] They have mainly focused on the H3.1 and H3.2 replicative histones and H3.3 and CENPA histone variants, while we tried to extend the scope to the whole histone H3 family as much as possible. We proposed that H3-alterations may cause poor outcomes and have particular clinical characteristics in patients with glioma.…”

“…The previous studies also reported that H3-alterations were associated with WHO grade and molecular patterns relevant to the biology of gliomas. 20 Patients with glioma with IDH mutation have a relatively good prognosis. 5 , 7 However, the IDH-mutant gliomas were often also molecularly heterogeneous at presentation, and in oligodendrogliomas, combined 1p and 19q loss were significantly associated with longer survival.…”

Differential Epigenetic Status and Responses to Stressors between Retinal Cybrids Cells with African versus European Mitochondrial DNA: Insights into Disease Susceptibilities

“…Garcia et al (2007) suggested that, based on this data, the histone variant H3 exhibits a higher degree of epigenetic modifications when compared to the histone variant H4 [ 73 ]. Moreover, it is the high expression of the nucleosome histone H3.3 that is associated with low-grade gliomas and may serve as a predictive marker [ 74 ]. Figure 4 A depicts the sites of epigenetic modification in the N-terminus segments of the histones H3 and H4.…”