Department of Neurology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Department of Tumour Immunology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Acta Neuropathol. 2024 Oct 9;148(1):50. doi: 10.1007/s00401-024-02811-0.
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.
准确的 IDH 突变型胶质瘤分级定义了患者的预后，并指导治疗路径。组织学分级具有挑战性，除了 IDH 突变型星形细胞瘤中 CDKN2A/B 纯合缺失外，没有其他用于分级的客观分子标志物。对包括在前瞻性 CATNON 试验中的原发性 IDH 突变型星形细胞瘤（n=138）进行了 RNA 测序，该试验旨在评估辅助和同期替莫唑胺的预后效果。我们将 RNA 测序数据与匹配的 DNA 甲基化和 NGS 数据进行了整合。我们还使用了包括在 TCGA 数据集中的 IDH 突变型星形细胞瘤的多组学数据，并在 GLASS-NL 研究中对匹配的原发性和复发性样本进行了验证。由于离散类别不能充分捕获这些肿瘤的分级，我们利用 DNA 甲基化谱基于 CNS 肿瘤分类器的分类评分生成了连续分级系数（CGC）。CGC 是独立的生存预测因子，优于当前的 WHO-CNS5 和基于甲基化的分类。我们的 RNA 测序分析揭示了四个不同的转录簇，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相关。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 突变型星形细胞瘤具有 DNA 甲基化特征，在 RNA 水平上与增加的细胞周期、肿瘤细胞去分化和细胞外基质重塑有关。这些联合分子特征可作为 IDH 突变型星形细胞瘤分级的客观标志物。
