DNA Methylation and Histone Modification in Low-Grade Gliomas: Current Understanding and Potential Clinical Targets

SIMPLE SUMMARY: Brain tumors comprise a large, varied group, with gliomas being the most common malignant tumors arising in the brain. This state-of-the-art review discusses the role of epigenetics in low-grade gliomas, i.e., those gliomas which are typically less invasive and have better survival rates than their high-grade counterparts. This paper is a summary of the current paradigms in DNA methylation and histone modification in low-grade gliomas, with their integration into the recently published WHO Classification for CNS Tumors, Fifth Edition. This paper, targeted towards a clinical audience, also describes the role of DNA methylation and histone modification in pathogenesis, clinical behavior, and outcomes of low-grade gliomas, with an emphasis on the potential therapeutic targets in associated cellular biomolecules, structures, and processes. ABSTRACT: Gliomas, the most common type of malignant primary brain tumor, were conventionally classified through WHO Grades I–IV (now 1–4), with low-grade gliomas being entities belonging to Grades 1 or 2. While the focus of the WHO Classification for Central Nervous System (CNS) tumors had historically been on histopathological attributes, the recently released fifth edition of the classification (WHO CNS5) characterizes brain tumors, including gliomas, using an integration of histological and molecular features, including their epigenetic changes such as histone methylation, DNA methylation, and histone acetylation, which are increasingly being used for the classification of low-grade gliomas. This review describes the current understanding of the role of DNA methylation, demethylation, and histone modification in pathogenesis, clinical behavior, and outcomes of brain tumors, in particular of low-grade gliomas. The review also highlights potential diagnostic and/or therapeutic targets in associated cellular biomolecules, structures, and processes. Targeting of MGMT promoter methylation, TET-hTDG-BER pathway, association of G-CIMP with key gene mutations, PARP inhibition, IDH and 2-HG-associated processes, TERT mutation and ARL9-associated pathways, DNA Methyltransferase (DNMT) inhibition, Histone Deacetylase (HDAC) inhibition, BET inhibition, CpG site DNA methylation signatures, along with others, present exciting avenues for translational research. This review also summarizes the current clinical trial landscape associated with the therapeutic utility of epigenetics in low-grade gliomas. Much of the evidence currently remains restricted to preclinical studies, warranting further investigation to demonstrate true clinical utility.