近年来，成人型弥漫性胶质瘤的分类经历了一场革命，其中特定的分子特征现在代表了IDH野生型胶质母细胞瘤、IDH突变型星形细胞瘤和IDH突变型1p/19q编码缺失少突胶质细胞瘤的诊断标准。随着 2021 年 WHO CNS 分类的推出，额外的分子改变现已纳入这些肿瘤的分级中，并与传统的组织学特征同等重要。然而，即使在这些已建立的肿瘤亚分类中，患者结果仍然存在很大的异质性，这是目前编码的分子改变无法解释的，特别是在 IDH 突变星形细胞瘤类别中。还存在显着的细胞间遗传和表观遗传异质性和可塑性，从而导致表型异质性，使这些肿瘤具有显着的适应性和鲁棒性，并对有效疗法的设计提出了重大障碍。在此，我们回顾了 IDH 的基础生物学、肿瘤发生和进展中遗传和表观遗传不稳定性的机制和后果，包括染色体不稳定性 (CIN)、微卫星不稳定性 (MSI)/错配修复 (MMR) 缺陷和表观遗传不稳定性。突变型星形细胞瘤。我们还讨论了最近的高分辨率转录组学研究对用单细胞分辨率定义肿瘤异质性的贡献。虽然瘤内异质性是弥漫性神经胶质瘤的一个众所周知的特征，但这些不同过程的贡献直到最近才被认为是肿瘤侵袭性的潜在驱动因素。 CIN 对患者生存具有独立的不利影响，类似于组织学分级和纯合 CDKN2A 缺失的影响，而 MMR 突变在单变量分析中仅与较差的总生存率相关，但与较高的组织学/分子分级和其他侵袭性特征高度相关。这些形式的基因组不稳定性可能会显着影响这些肿瘤的自然进展、对治疗的反应以及患者的最终临床结果，是潜在的可测量特征，有助于诊断、分级、预后和个性化治疗的开发。© 2024 . 作者。

In recent years, the classification of adult-type diffuse gliomas has undergone a revolution, wherein specific molecular features now represent defining diagnostic criteria of IDH-wild-type glioblastomas, IDH-mutant astrocytomas, and IDH-mutant 1p/19q-codeleted oligodendrogliomas. With the introduction of the 2021 WHO CNS classification, additional molecular alterations are now integrated into the grading of these tumors, given equal weight to traditional histologic features. However, there remains a great deal of heterogeneity in patient outcome even within these established tumor subclassifications that is unexplained by currently codified molecular alterations, particularly in the IDH-mutant astrocytoma category. There is also significant intercellular genetic and epigenetic heterogeneity and plasticity with resulting phenotypic heterogeneity, making these tumors remarkably adaptable and robust, and presenting a significant barrier to the design of effective therapeutics. Herein, we review the mechanisms and consequences of genetic and epigenetic instability, including chromosomal instability (CIN), microsatellite instability (MSI)/mismatch repair (MMR) deficits, and epigenetic instability, in the underlying biology, tumorigenesis, and progression of IDH-mutant astrocytomas. We also discuss the contribution of recent high-resolution transcriptomics studies toward defining tumor heterogeneity with single-cell resolution. While intratumoral heterogeneity is a well-known feature of diffuse gliomas, the contribution of these various processes has only recently been considered as a potential driver of tumor aggressiveness. CIN has an independent, adverse effect on patient survival, similar to the effect of histologic grade and homozygous CDKN2A deletion, while MMR mutation is only associated with poor overall survival in univariate analysis but is highly correlated with higher histologic/molecular grade and other aggressive features. These forms of genomic instability, which may significantly affect the natural progression of these tumors, response to therapy, and ultimately clinical outcome for patients, are potentially measurable features which could aid in diagnosis, grading, prognosis, and development of personalized therapeutics.© 2024. The Author(s).