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

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.