Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Germany.
Acta Neuropathol. 2010 Dec;120(6):707-18. doi: 10.1007/s00401-010-0781-z. Epub 2010 Nov 19.
WHO grading of human brain tumors extends beyond a strictly histological grading system by providing a basis predictive for the clinical behavior of the respective neoplasm. For example, patients with glioblastoma WHO grade IV usually show a less favorable clinical course and receive more aggressive first-line treatment than patients with anaplastic astrocytoma WHO grade III. Here we provide evidence that the IDH1 status is more prognostic for overall survival than standard histological criteria that differentiate high-grade astrocytomas. We sequenced the isocitrate dehydrogenase 1 gene (IDH1) at codon 132 in 382 patients with anaplastic astrocytoma and glioblastoma from the NOA-04 trial and from a prospective translational cohort study of the German Glioma Network. Patients with anaplastic astrocytomas carried IDH1 mutations in 60%, and patients with glioblastomas in 7.2%. IDH1 was the most prominent single prognostic factor (RR 2.7; 95% CI 1.6-4.5) followed by age, diagnosis and MGMT. The sequence from more favorable to poorer outcome was (1) anaplastic astrocytoma with IDH1 mutation, (2) glioblastoma with IDH1 mutation, (3) anaplastic astrocytoma without IDH1 mutation and (4) glioblastoma without IDH1 mutation (p < 0.0001). In this combined set of anaplastic astrocytomas and glioblastomas both, IDH1 mutation and IDH1 expression status were of greater prognostic relevance than histological diagnosis according to the current WHO classification system. Our data indicate that much of the prognostic significance of patient age is due to the predominant occurrence of IDH1 mutations in younger patients. Immunohistochemistry using a mutation-specific antibody recognizing the R132H mutation yielded similar results. We propose to complement the current WHO classification and grading of high-grade astrocytic gliomas by the IDH1 mutation status and to use this combined histological and molecular classification in future clinical trials.
世界卫生组织（WHO）对人脑肿瘤的分级不仅超出了严格的组织学分级系统，还为相应肿瘤的临床行为提供了预测基础。例如，胶质母细胞瘤 WHO 分级 IV 级的患者通常表现出较差的临床病程，并接受比间变性星形细胞瘤 WHO 分级 III 级患者更具侵袭性的一线治疗。在这里，我们提供的证据表明，IDH1 状态比区分高级别星形细胞瘤的标准组织学标准更能预测总生存期。我们对来自 NOA-04 试验和德国神经胶质瘤网络前瞻性转化队列研究的 382 例间变性星形细胞瘤和胶质母细胞瘤患者的异柠檬酸脱氢酶 1 基因（IDH1）第 132 位密码子进行了测序。间变性星形细胞瘤患者中有 60%携带 IDH1 突变，胶质母细胞瘤患者中有 7.2%携带 IDH1 突变。IDH1 是最显著的单一预后因素（RR 2.7；95%CI 1.6-4.5），其次是年龄、诊断和 MGMT。从预后较好到较差的序列为（1）携带 IDH1 突变的间变性星形细胞瘤，（2）携带 IDH1 突变的胶质母细胞瘤，（3）不携带 IDH1 突变的间变性星形细胞瘤，（4）不携带 IDH1 突变的胶质母细胞瘤（p<0.0001）。在这组间变性星形细胞瘤和胶质母细胞瘤中，IDH1 突变和 IDH1 表达状态的预后相关性均高于当前 WHO 分类系统的组织学诊断。我们的数据表明，患者年龄的大部分预后意义归因于 IDH1 突变在年轻患者中更为常见。使用识别 R132H 突变的突变特异性抗体进行免疫组织化学检测得到了类似的结果。我们建议通过 IDH1 突变状态补充当前高级别星形胶质细胞瘤的 WHO 分类和分级，并在未来的临床试验中使用这种组合的组织学和分子分类。
