IDH1/2 gene hotspot mutations in central nervous system tumours: analysis of 922 Chinese patients
IDH1/2 gene hotspot mutations in central nervous system tumours: analysis of 922 Chinese patients
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中枢神经系统肿瘤IDH1/2基因热点突变：922例中国患者分析
DOI：
10.1016/j.pathol.2016.07.010
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发表时间：
2016-12-01
期刊：
影响因子：
4.5
通讯作者：
Zhou, Qiao
中科院分区：
文献类型：
--
作者：
Chen, Ni;Yu, Tianpin;Zhou, Qiao
异柠檬酸脱氢酶1 （IDH1）或2 （IDH2）基因突变已被确定为星形细胞瘤和少突胶质细胞瘤发展的早期分子事件。关于IDH1/2突变在中国患者中的状态和流行的数据是有限的。在此，我们报告来自中国主要医疗中心华西医院的数据。对1011例患者（包括922例中枢神经系统肿瘤和89例非肿瘤性中枢神经系统病变）的IDH1（R132H）突变进行免疫组化分析，并对其中570例患者的IDH1（R132H）基因突变进行pcr直接测序。检测p53、EGFR、PTEN、Ki-67与临床病理特征及免疫组化表达的相关性。我们的数据显示，IDH1/2突变存在于少突胶质细胞瘤、间变性少突胶质细胞瘤、弥漫性或间变性星形细胞瘤和胶质母细胞瘤中，其频率呈下降趋势，但不存在于其他类型的中枢神经系统肿瘤或非肿瘤性病变中。IDH1（R132）突变在少突胶质细胞瘤中最常见（57/62,91.9%），其中IDH1（R132H）突变是最常见的突变形式。在测序分析的570个样本中，每种罕见突变（R132C、R132G、R132L和R132S）仅鉴定出一例。年龄小、p53低表达、Ki-67指数低与IDH1突变状态显著相关（p = 0.000）。所有IDH1（R132）突变的肿瘤都位于幕上，其中额叶是IDH1突变胶质瘤最常见的部位。本系列中仅检测到3例IDH2（R172）突变病例。459例弥漫性浸润胶质瘤患者的单因素生存分析显示，IDH1突变以及更经典的预后指标（年龄、WHO分级、p53和Ki-67指数）具有预后意义。Cox比例风险回归模型多因素分析显示，缺乏IDH1突变是无进展生存[相对危险度(RR) = 2.450, 95%可信区间(CI) = 1.351-4.444]和疾病特异性生存（RR = 2.489, 95% CI = 1.155-5.363）的独立预后因素。
Mutations of isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) genes have been identified as early molecular events in the development of astrocytomas and oligodendrogliomas. Data regarding the status and prevalence of IDH1/2 mutations in Chinese patients are limited. Herein we report our data from West China Hospital, a major Chinese medical centre. IDH1(R132H) mutation was analysed by immunohistochemistry with the mutation-specific IDH1(R132H) antibody in 1011 patients, including 922 central nervous system (CNS) tumours and 89 non-neoplastic CNS lesions, and PCR-based direct sequencing of IDH1/2 gene mutation in 570 of these samples. Correlation with clinicopathological features and immunohistochemical expression of p53, EGFR, PTEN and Ki-67 was examined. Our data showed that IDH1/2 mutation was present in oligodendrogliomas, anaplastic oligodendrogliomas, diffuse or anaplastic astrocytomas, and glioblastomas, with decreasing frequency, but not in other types of CNS tumours or non-neoplastic lesions examined. IDH1(R132) mutation was most frequent in oligodendrogliomas (57/62, 91.9%), with IDH1(R132H) mutation as the most frequent mutation form. Only one case for each of the rare mutations (R132C, R132G, R132L, and R132S) was identified in the 570 samples analysed by sequencing. Younger age, low expression of p53 and low Ki-67 index were significantly correlated with IDH1 mutation status (p = 0.000). All tumours with IDH1(R132) mutations were supratentorial, with frontal lobe as the most frequent site for IDH-mutated gliomas. Only three IDH2(R172) mutation cases were detected in this series. Univariate survival analysis in 459 glioma patients with diffusely infiltrating gliomas showed that IDH1 mutations as well as the more classical prognosticators (age, WHO grade, p53 and Ki-67 index) were of prognostic significance. Multivariate analysis by Cox proportional hazard regression model demonstrated that lack of IDH1 mutation was an independent prognostic factor for both progression-free survival [relative risk (RR) = 2.450, 95% confidence interval (CI) = 1.351-4.444] and diseasespecific survival (RR = 2.489, 95% CI = 1.155-5.363).