DNA methylation analysis reveals an epigenetic signature distinctive of high-grade oligodendroglioma

IF 9.3 1区医学 Q1 CLINICAL NEUROLOGY

Acta Neuropathologica Pub Date : 2025-08-23 DOI:10.1007/s00401-025-02926-y

Katharina Johanna Weber, Mareike Dettki, Marco Münzberg, Pia Susann Zeiner, Marie-Thérèse Forster, Eike Steidl, Iris Divé, Patrick Nikolaus Harter, Michael Scherer

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Abstract

IDH-mutant gliomas represent a subtype of diffuse gliomas that primarily affect patients in early to mid-adolescence. These tumors are classified into three distinct CNS WHO grades of malignancy. Accurate grading is essential for selecting an appropriate treatment maximizing anti-tumor efficacy while minimizing adverse effects. However, grading of oligodendrogliomas with 1p/19q codeletion currently relies on qualitative tumor characteristics that may be influenced by observer subjectivity, sampling bias, and tumor heterogeneity. This study aimed to explore DNA methylation-based tumor deconvolution into latent methylation components (LMCs) to evaluate their potential as objective grading tools in a cohort of 137 IDH-mutant gliomas. LMCs were analyzed in relation to malignancy markers, cellular composition, and underlying methylation signatures of the chromatin landscape. Glioma subtypes were associated with distinct LMCs. Two LMCs correlated with higher cellular density and advanced epigenetic age as well as with microvascular proliferation, necrosis, and epigenetically defined high-grade astrocytoma. The epigenetic patterns defining high-grade astrocytoma or oligodendroglioma, respectively, were similar. Higher-grade oligodendrogliomas, identified by LMC-based grading, were associated with more copy number alterations. Among patients of an external cohort who died during the assessment period, higher LMC1 proportions were associated with poorer overall survival. Therefore, LMCs hold the potential to support IDH-mutant glioma grading by incorporating objective epigenetic markers.

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DNA甲基化分析揭示了高级别少突胶质细胞瘤特有的表观遗传特征

idh突变型胶质瘤是弥漫性胶质瘤的一种亚型，主要影响青少年早期至中期的患者。这些肿瘤被划分为三个不同的中枢神经系统WHO恶性肿瘤等级。准确的分级对于选择合适的治疗方法至关重要，可以最大限度地提高抗肿瘤疗效，同时减少不良反应。然而，编码1p/19q的少突胶质瘤的分级目前依赖于定性肿瘤特征，可能受到观察者主观性、抽样偏差和肿瘤异质性的影响。本研究旨在探索基于DNA甲基化的肿瘤反卷积成潜在甲基化成分（lmc），以评估它们在137例idh突变胶质瘤队列中作为客观分级工具的潜力。我们分析了lmc与恶性肿瘤标志物、细胞组成和潜在的染色质甲基化特征的关系。胶质瘤亚型与不同的lmc相关。两种lmc与较高的细胞密度和较晚的表观遗传年龄以及微血管增生、坏死和表观遗传定义的高级别星形细胞瘤相关。定义高级别星形细胞瘤或少突胶质细胞瘤的表观遗传模式是相似的。高级别少突胶质细胞瘤，通过基于lmc的分级识别，与更多的拷贝数改变相关。在评估期间死亡的外部队列患者中，较高的LMC1比例与较差的总生存期相关。因此，lmc具有通过结合客观表观遗传标记来支持idh突变胶质瘤分级的潜力。

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来源期刊

Acta Neuropathologica 医学-病理学

CiteScore

23.70

自引率

3.90%

发文量

118

审稿时长

4-8 weeks

期刊介绍： Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.