The role of histone modifications and telomere alterations in the pathogenesis of diffuse gliomas in adults and children

Abstract

Genetic profiling is an increasingly useful tool for sub-classification of gliomas in adults and children. Specific gene mutations, structural rearrangements, DNA methylation patterns, and gene expression profiles are now recognized to define molecular subgroups of gliomas that arise in distinct anatomic locations and patient age groups, and also provide a better prediction of clinical outcomes for glioma patients compared to histologic assessment alone. Understanding the role of these distinctive genetic alterations in gliomagenesis is also important for the development of potential targeted therapeutic interventions. Mutations including K27M and G34R/V that affect critical amino acids within the N-terminal tail of the histone H3 variants, H3.3 and H3.1 (encoded by H3F3A and HIST1H3B genes), are prime examples of mutations in diffuse gliomas with characteristic clinical associations that can help diagnostic classification and guide effective patient management. These histone H3 mutations frequently co-occur with inactivating mutations in ATRX in association with alternative lengthening of telomeres. Telomere length can also be maintained through upregulation of telomerase reverse transcriptase (TERT) expression driven by mutation within the TERT gene promoter region, an alteration most commonly found in oligodendrogliomas and primary glioblastomas arising in adults. Interestingly, the genetic alterations perturbing histone and telomere function in pediatric gliomas tend to be different from those present in adult tumors. We present a review of these mutations affecting the histone code and telomere length, highlighting their importance in prognosis and as targets for novel therapeutics in the treatment of diffuse gliomas.

Therapeutic Targeting of Histone Modifications in Adult and Pediatric High-Grade Glioma

“…H3F3A/ATRX-DAXX/TP53 mutations are strongly associated with alternative lengthening of telomeres, a telomerase-independent telomere maintenance mechanism that could allow unlimited cellular proliferation in pediatric glioblastoma (13, 33, 37, 38). …”

Reconstructing the Molecular Life History of Gliomas

“…Contrary to adult IDH-wildtype diffuse glioma, H3-mutant malignant pediatric glioma frequently demonstrate ALT [185], and several studies reported frequent co-occurrence of ATRX mutations in both H3 K27 and G34 mutant gliomas. However, reports of co-occurrence vary between 30% and 60% for K27 and 75% to 100% for G34, suggesting that there is a role for telomerase in many of these tumors as well [186].…”

Mutant RUNX1 and histone tales

“…The results from this work fit within a broader literature that has demonstrated the oncogenic properties of H3K27 mutations in diffuse midline gliomas. [6][7][8] In these tumors, the H3K27M mutation also results in global loss of H3K27 methylation levels. Given the importance of chromatin structure in transcription factor binding, several questions remain to define how H3K27 mutations and lower K27me levels cooperate with RUNX1 mutations: where are the mutant histones located in relation to RUNX1 binding sites?…”

“…5 The hyperhemolysis paradigm (HHP), through which it is hypothesized that chronic hemolysis in SCD sequentially causes increased cell-free plasma hemoglobin, nitric oxide biodeficiency, endothelial dysfunction, pulmonary hypertension, and vascular complications, led to the concept of 2 different subphenotypes of SCD: one characterized by the constellation of high hemoglobin levels, vaso-occlusive pain crises, acute chest syndrome, and osteonecrosis and the other by hemolysis, pulmonary hypertension, priapism, leg ulcers, and stroke (see figure). 6,7 The controversy involves both the concept that there might be a clear divide between these 2 subphenotypes and the extent of the overlap between them. Furthermore, studies supporting the HHP have mostly been conducted in the United States, and to date, its appraisal in the context of SCD in Africa has been extremely limited.…”

“…Furthermore, an important omission in this study was the lack of data on a-thalassemia, an important modifier of SCD that might potentially shift patients from one subphenotype to the other. 7 …”