Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, 8091, Zurich, Switzerland.
Department of Neurology, University of Zurich, Zurich, Switzerland.
Acta Neuropathol. 2024 Jan 6;147(1):11. doi: 10.1007/s00401-023-02662-1.
Prognostic factors and standards of care for astrocytoma, isocitrate dehydrogenase (IDH)-mutant, CNS WHO grade 4, remain poorly defined. Here we sought to explore disease characteristics, prognostic markers, and outcome in patients with this newly defined tumor type. We determined molecular biomarkers and assembled clinical and outcome data in patients with IDH-mutant astrocytomas confirmed by central pathology review. Patients were identified in the German Glioma Network cohort study; additional cohorts of patients with CNS WHO grade 4 tumors were identified retrospectively at two sites. In total, 258 patients with IDH-mutant astrocytomas (114 CNS WHO grade 2, 73 CNS WHO grade 3, 71 CNS WHO grade 4) were studied. The median age at diagnosis was similar for all grades. Karnofsky performance status at diagnosis inversely correlated with CNS WHO grade (p < 0.001). Despite more intensive treatment upfront with higher grade, CNS WHO grade was strongly prognostic: median overall survival was not reached for grade 2 (median follow-up 10.4 years), 8.1 years (95% CI 5.4-10.8) for grade 3, and 4.7 years (95% CI 3.4-6.0) for grade 4. Among patients with CNS WHO grade 4 astrocytoma, median overall survival was 5.5 years (95% CI 4.3-6.7) without (n = 58) versus 1.8 years (95% CI 0-4.1) with (n = 12) homozygous CDKN2A deletion. Lower levels of global DNA methylation as detected by LINE-1 methylation analysis were strongly associated with CNS WHO grade 4 (p < 0.001) and poor outcome. MGMT promoter methylation status was not prognostic for overall survival. Histomolecular stratification based on CNS WHO grade, LINE-1 methylation level, and CDKN2A status revealed four subgroups of patients with significantly different outcomes. In conclusion, CNS WHO grade, global DNA methylation status, and CDKN2A homozygous deletion are prognostic in patients with IDH-mutant astrocytoma. Combination of these parameters allows for improved prediction of outcome. These data aid in designing upcoming trials using IDH inhibitors.
间变性星形细胞瘤，异柠檬酸脱氢酶（IDH）突变型，中枢神经系统世界卫生组织（CNS）分级 4 的预后因素和治疗标准仍定义不明确。在这里，我们试图探索这种新定义的肿瘤类型的疾病特征、预后标志物和结果。我们通过中心病理复查确定了 IDH 突变型星形细胞瘤患者的分子生物标志物，并收集了临床和结局数据。患者在德国神经胶质瘤网络队列研究中被确定；在两个地点回顾性地确定了另外两组 CNS 分级 4 肿瘤患者。共有 258 名 IDH 突变型星形细胞瘤患者（114 名 CNS 分级 2，73 名 CNS 分级 3，71 名 CNS 分级 4）接受了研究。所有级别患者的中位诊断年龄相似。诊断时的卡氏功能状态与 CNS 分级呈负相关（p<0.001）。尽管随着级别升高，初始治疗更为强化，但 CNS 分级仍是强烈的预后因素：2 级的中位总生存期未达到（中位随访 10.4 年），3 级为 8.1 年（95%CI 5.4-10.8），4 级为 4.7 年（95%CI 3.4-6.0）。在 CNS 分级 4 级星形细胞瘤患者中，无（n=58）和有（n=12）同源性 CDKN2A 缺失的中位总生存期分别为 5.5 年（95%CI 4.3-6.7）和 1.8 年（95%CI 0-4.1）。通过 LINE-1 甲基化分析检测到的较低水平的全基因组 DNA 甲基化与 CNS 分级 4（p<0.001）和不良结局密切相关。MGMT 启动子甲基化状态与总生存期无相关性。基于 CNS 分级、LINE-1 甲基化水平和 CDKN2A 状态的组织分子分层揭示了具有显著不同结局的四个患者亚组。总之，CNS 分级、全基因组 DNA 甲基化状态和 CDKN2A 纯合缺失在 IDH 突变型星形细胞瘤患者中具有预后意义。这些参数的组合可提高对结局的预测。这些数据有助于设计使用 IDH 抑制剂的后续试验。
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