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.

星形细胞瘤、异柠檬酸脱氢酶 (IDH) 突变、CNS WHO 4 级的预后因素和护理标准仍然不明确。在这里，我们试图探索这种新定义的肿瘤类型患者的疾病特征、预后标志物和结果。我们确定了分子生物标志物，并收集了经中央病理学审查证实的 IDH 突变星形细胞瘤患者的临床和结果数据。德国神经胶质瘤网络队列研究中确定了患者；在两个地点回顾性鉴定了另外一组患有中枢神经系统 WHO 4 级肿瘤的患者。总共对 258 名 IDH 突变型星形细胞瘤患者（114 名 CNS WHO 2 级、73 名 CNS WHO 3 级、71 名 CNS WHO 4 级）进行了研究。所有年级的诊断中位年龄相似。诊断时的卡诺夫斯基表现状态与 CNS WHO 分级呈负相关 ( p  < 0.001)。尽管在较高级别上预先进行了更强化的治疗，但 CNS WHO 级别具有很强的预后性：2 级未达到中位总生存期（中位随访时间 10.4 年），3 级为 8.1 年（95% CI 5.4-10.8），4.7 年4 级的中枢神经系统 WHO 4 级星形细胞瘤患者的中位总生存期为 5.5 年（95% CI 4.3-6.7），无（n  = 58）则为1.8 年（95% CI 0 –4.1) ( n  = 12) 纯合CDKN2A缺失。LINE-1甲基化分析检测到的整体 DNA 甲基化水平较低与 CNS WHO 4 级 ( p  < 0.001) 和不良预后密切相关。MGMT启动子甲基化状态不能预测总生存期。基于 CNS WHO 分级、LINE-1甲基化水平和CDKN2A状态的组织分子分层揭示了四个患者亚组，其结果显着不同。总之，CNS WHO 分级、整体 DNA 甲基化状态和CDKN2A纯合缺失对于 IDH 突变型星形细胞瘤患者具有预后意义。这些参数的组合可以改进对结果的预测。这些数据有助于设计即将进行的使用 IDH 抑制剂的试验。