Ozair Ahmad, Bhat Vivek, Alisch Reid S, Khosla Atulya A, Kotecha Rupesh R, Odia Yazmin, McDermott Michael W, Ahluwalia Manmeet S
Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176, USA.
Faculty of Medicine, King George's Medical University, Lucknow 226003, India.
Cancers (Basel). 2023 Feb 20;15(4):1342. doi: 10.3390/cancers15041342.
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.
胶质瘤是最常见的原发性恶性脑肿瘤，传统上通过世界卫生组织（WHO）I-IV级（现1-4级）进行分类，低级别胶质瘤属于1级或2级实体。虽然WHO中枢神经系统（CNS）肿瘤分类的重点历史上一直是组织病理学特征，但最近发布的第五版分类（WHO CNS5）使用组织学和分子特征的整合来对包括胶质瘤在内的脑肿瘤进行特征描述，这些特征包括表观遗传变化，如组蛋白甲基化、DNA甲基化和组蛋白乙酰化，它们越来越多地被用于低级别胶质瘤的分类。本综述描述了目前对DNA甲基化、去甲基化和组蛋白修饰在脑肿瘤，特别是低级别胶质瘤的发病机制、临床行为和预后中的作用的理解。该综述还强调了相关细胞生物分子、结构和过程中的潜在诊断和/或治疗靶点。针对MGMT启动子甲基化、TET-hTDG-BER途径、G-CIMP与关键基因突变的关联、PARP抑制、IDH和2-HG相关过程、TERT突变和ARL9相关途径、DNA甲基转移酶（DNMT）抑制、组蛋白去乙酰化酶（HDAC）抑制、BET抑制、CpG位点DNA甲基化特征等，为转化研究提供了令人兴奋的途径。本综述还总结了目前与表观遗传学在低级别胶质瘤治疗效用相关的临床试验情况。目前的许多证据仍局限于临床前研究，需要进一步研究以证明其真正的临床效用。
