Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas
Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas
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DOI：
10.1007/s00401-010-0781-z
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发表时间：
2010-12-01
影响因子：
12.7
通讯作者：
von Deimling, Andreas
中科院分区：
文献类型：
--
作者：
Hartmann, Christian;Hentschel, Bettina;von Deimling, Andreas
世卫组织对人脑肿瘤的分级超越了严格的组织学分级系统，为相应肿瘤的临床行为提供了预测基础。例如，与间变性星形细胞瘤患者相比，WHO IV级胶质母细胞瘤患者的临床病程通常较差，并接受更积极的一线治疗。在这里，我们提供的证据表明，与区分高级别星形细胞瘤的标准组织学标准相比，IDH1状态更能预测总体生存率。我们从NOA-04试验和德国胶质瘤网络的一项前瞻性翻译队列研究中对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是最显著的单因素预后因素(RR2.7；95%CI 1.6~4.5)，其次是年龄、诊断和MGMT。从好到差的顺序是：(1)间变性星形细胞瘤伴IDH1突变，(2)胶质母细胞瘤伴IDH1突变，(3)间变性星形细胞瘤不伴IDH1突变，(4)胶质母细胞瘤不伴IDH1突变(p<；0.0001)。在这组间变性星形细胞瘤和胶质母细胞瘤中，根据目前的WHO分类系统，IDH1突变和IDH1表达状态比组织学诊断具有更大的预后相关性。我们的数据表明，患者年龄的大部分预后意义是由于IDH1突变主要发生在较年轻的患者中。使用识别R132H突变的突变特异性抗体的免疫组织化学也产生了类似的结果。我们建议通过IDH1突变状态来补充目前WHO对高级别星形细胞胶质瘤的分类和分级，并在未来的临床试验中使用这种联合的组织学和分子分类。
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.