Authors' Affiliations: Department of Neuropathology, Institute of Pathology, Hannover Medical School, Hannover; Department of Neuropathology, and German Cancer Research Center (DKFZ), Clinical Cooperation Unit Neuropathology, University Hospital of Heidelberg, Institute for Pathology, Heidelberg; Institute for Medical Informatics, Statistics and Epidemiology, University Leipzig; Departments of Neurosurgery and Neuropathology, University of Bonn, Bonn; Department of Neurosurgery, University of Hamburg, Hamburg; Department of Neurosurgery, University of Dresden, Dresden; Department of Neurosurgery, University of Munich, Munich; Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany; and Department of Neurology, University Hospital Zurich, and Neuroscience Center Zurich, University of Zurich, Zurich, Switzerland.
Clin Cancer Res. 2013 Sep 15;19(18):5146-57. doi: 10.1158/1078-0432.CCR-13-0017. Epub 2013 Aug 5.
The determinants of long-term survival in glioblastoma have remained largely obscure. Isocitrate dehydrogenase (IDH) 1 or 2 mutations are common in World Health Organization (WHO) grades II and III gliomas, but rare in primary glioblastomas, and associated with longer survival.
We compared clinical and molecular characteristics of 69 patients with centrally confirmed glioblastoma and survival >36 months (LTS-36), including 33 patients surviving >60 months (LTS-60), with 257 patients surviving <36 months. MGMT promoter methylation, 1p/19q codeletions, EGFR amplification, TP53 mutations, and IDH1/2 mutations were determined by standard techniques.
The rate of IDH1/2 mutations in LTS-36 patients was 34% (23 of 67 patients) as opposed to 4.3% in controls (11 of 257 patients). Long-term survivors with IDH1/2-mutant glioblastomas were younger, had almost no EGFR amplifications, but exhibited more often 1p/19q codeletions and TP53 mutations than LTS patients with IDH1/2 wild-type glioblastomas. Long-term survivors with IDH1/2 wild-type showed no distinguishing features from other patients with IDH1/2 wild-type glioblastomas except for a higher rate of MGMT promoter methylation. Similarly, among 11 patients with IDH1/2-mutant glioblastomas without long-term survival, the only difference to IDH1/2-mutant long-term survivors was less-frequent MGMT promoter methylation. Compared with LTS-36 patients, LTS-60 patients had less frequently TP53 mutations and radiotherapy alone as initial treatment.
IDH1/2 mutations define a subgroup of tumors of LTS patients that exhibit molecular characteristics of WHO grade II/III gliomas and secondary glioblastomas. Determinants of LTS with IDH1/2 wild-type glioblastomas, which exhibit typical molecular features of primary glioblastomas, beyond MGMT promoter methylation, remain to be identified.
胶质母细胞瘤患者长期生存的决定因素在很大程度上仍不清楚。异柠檬酸脱氢酶（IDH）1 或 2 突变在世界卫生组织（WHO）分级 II 和 III 级胶质瘤中很常见，但在原发性胶质母细胞瘤中很少见，与更长的生存时间相关。
我们比较了 69 例经中心证实的胶质母细胞瘤患者的临床和分子特征，这些患者的生存时间超过 36 个月（LTS-36），包括 33 例生存时间超过 60 个月（LTS-60）的患者，与 257 例生存时间<36 个月的患者进行比较。通过标准技术确定 MGMT 启动子甲基化、1p/19q 缺失、EGFR 扩增、TP53 突变和 IDH1/2 突变。
LTS-36 患者中 IDH1/2 突变的发生率为 34%（67 例患者中有 23 例），而对照组（257 例患者中有 11 例）为 4.3%。具有 IDH1/2 突变的长期生存者较年轻，几乎没有 EGFR 扩增，但与具有 IDH1/2 野生型的 LTS 患者相比，更常出现 1p/19q 缺失和 TP53 突变。具有 IDH1/2 野生型的长期生存者除了 MGMT 启动子甲基化率较高外，与其他具有 IDH1/2 野生型的胶质母细胞瘤患者没有明显区别。同样，在 11 例无长期生存的 IDH1/2 突变型胶质母细胞瘤患者中，与 IDH1/2 突变型长期生存者唯一的区别是 MGMT 启动子甲基化频率较低。与 LTS-36 患者相比，LTS-60 患者较少接受 TP53 突变和单独放疗作为初始治疗。
IDH1/2 突变定义了一组具有 LTS 患者的肿瘤亚群，这些肿瘤具有 WHO 分级 II/III 级胶质瘤和继发性胶质母细胞瘤的分子特征。具有 IDH1/2 野生型的 LTS 患者的决定因素，除了 MGMT 启动子甲基化之外，还具有典型的原发性胶质母细胞瘤的分子特征，仍有待确定。
