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IDH-野生型胶质母细胞瘤的定义诊断标准,IDH突变星形细胞瘤,和IDH突变型1p/19q缺失的少突胶质细胞瘤。随着2021年世界卫生组织中枢神经系统分类的引入,额外的分子改变现在被整合到这些肿瘤的分级中,与传统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,患者的预后仍然存在大量异质性,而这些肿瘤亚分类是目前编码的分子改变无法解释的。特别是在IDH突变型星形细胞瘤类别中。还存在显著的细胞间遗传和表观遗传异质性和可塑性,导致表型异质性,使这些肿瘤具有显著的适应性和健壮,并为有效疗法的设计提供了重大障碍。在这里,我们回顾了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,在潜在的生物学中,肿瘤发生,以及IDH突变型星形细胞瘤的进展。我们还讨论了最近的高分辨率转录组学研究对使用单细胞分辨率定义肿瘤异质性的贡献。虽然肿瘤内异质性是弥漫性神经胶质瘤的一个众所周知的特征,这些不同过程的作用直到最近才被认为是肿瘤侵袭性的潜在驱动因素.CIN有一个独立的,对患者生存的不利影响,与组织学分级和纯合CDKN2A缺失的效果相似,而在单变量分析中,MMR突变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,这可能会显著影响这些肿瘤的自然进展,对治疗的反应,以及最终患者的临床结果,是可以帮助诊断的潜在可测量特征,分级,预后,和个性化治疗的发展。
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.