表观遗传景观重组和胚胎发育基因的重新激活与 IDH 突变星形细胞瘤的恶性程度有关

IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Acta Neuropathologica Pub Date : 2024-10-09 DOI:10.1007/s00401-024-02811-0
Santoesha A. Ghisai, Levi van Hijfte, Wies R. Vallentgoed, C. Mircea S. Tesileanu, Iris de Heer, Johan M. Kros, Marc Sanson, Thierry Gorlia, Wolfgang Wick, Michael A. Vogelbaum, Alba A. Brandes, Enrico Franceschi, Paul M. Clement, Anna K. Nowak, Vassilis Golfinopoulos, Martin J. van den Bent, Pim J. French, Youri Hoogstrate
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引用次数: 0

摘要

IDH突变胶质瘤的准确分级可确定患者的预后并指导治疗方案。组织学分级具有挑战性,除了 IDH 突变星形细胞瘤中的 CDKN2A/B 基因同源缺失外,目前还没有其他用于分级的客观分子标记物。我们对前瞻性CATNON试验中的原发性IDH突变星形细胞瘤(n = 138)进行了RNA测序,该试验旨在评估替莫唑胺辅助治疗和同期治疗对预后的影响。我们将 RNA 序列数据与匹配的 DNA 甲基化和 NGS 数据进行了整合。我们还使用了TCGA数据集中IDH突变星形细胞瘤的多组学数据,并验证了GLASS-NL研究中匹配的原发样本和复发样本的结果。由于离散分级不能充分捕捉这些肿瘤的分级,我们利用DNA甲基化图谱,根据中枢神经系统肿瘤分类器的分类分数生成连续分级系数(CGC)。CGC 是生存率的独立预测指标,优于目前的 WHO-CNS5 和基于甲基化的分类。我们的 RNA 序列分析发现了四个不同的转录集群,它们分别与:(i) 细胞周期基因的上调;(ii) 神经胶质分化基因的下调;(iii) 胚胎发育基因(如 HOX、PAX 和 TBX)的上调和 (iv) 细胞外基质基因的上调有关。胚胎发育基因的上调与这些基因附近 CpG 岛甲基化的特定增加有关。高级别 IDH 突变星形细胞瘤的 DNA 甲基化特征在 RNA 水平上与细胞周期、肿瘤细胞去分化和细胞外基质重塑的增加有关。这些综合分子特征可作为 IDH 突变星形细胞瘤分级的客观标记。
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Epigenetic landscape reorganisation and reactivation of embryonic development genes are associated with malignancy in IDH-mutant astrocytoma

Accurate grading of IDH-mutant gliomas defines patient prognosis and guides the treatment path. Histological grading is challenging, and aside from CDKN2A/B homozygous deletions in IDH-mutant astrocytomas, there are no other objective molecular markers used for grading. RNA-sequencing was conducted on primary IDH-mutant astrocytomas (n = 138) included in the prospective CATNON trial, which was performed to assess the prognostic effect of adjuvant and concurrent temozolomide. We integrated the RNA-sequencing data with matched DNA-methylation and NGS data. We also used multi-omics data from IDH-mutant astrocytomas included in the TCGA dataset and validated results on matched primary and recurrent samples from the GLASS-NL study. Since discrete classes do not adequately capture grading of these tumours, we utilised DNA-methylation profiles to generate a Continuous Grading Coefficient (CGC) based on classification scores from a CNS-tumour classifier. CGC was an independent predictor of survival outperforming current WHO-CNS5 and methylation-based classification. Our RNA-sequencing analysis revealed four distinct transcription clusters that were associated with (i) upregulation of cell cycling genes; (ii) downregulation of glial differentiation genes; (iii) upregulation of embryonic development genes (e.g. HOX, PAX, and TBX) and (iv) upregulation of extracellular matrix genes. The upregulation of embryonic development genes was associated with a specific increase of CpG island methylation near these genes. Higher grade IDH-mutant astrocytomas have DNA-methylation signatures that, on the RNA level, are associated with increased cell cycling, tumour cell de-differentiation and extracellular matrix remodelling. These combined molecular signatures can serve as an objective marker for grading of IDH-mutant astrocytomas.

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来源期刊
Acta Neuropathologica
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.
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