IDH1 and IDH2 mutations in gliomas.
IDH1 and IDH2 mutations in gliomas.
复制标题
DOI：
10.1056/nejmoa0808710
复制
发表时间：
2009-02-19
期刊：
影响因子：
--
通讯作者：
Bigner DD
中科院分区：
文献类型：
--
作者：
Yan H;Parsons DW;Jin G;McLendon R;Rasheed BA;Yuan W;Kos I;Batinic-Haberle I;Jones S;Riggins GJ;Friedman H;Friedman A;Reardon D;Herndon J;Kinzler KW;Velculescu VE;Vogelstein B;Bigner DD
最近对胶质母细胞瘤（世界卫生组织[WHO] IV级胶质瘤）的全基因组突变分析显示，在一部分此类肿瘤中，异柠檬酸脱氢酶1基因（IDH1）发生体细胞突变，最常见于已知从低级别胶质瘤（继发性胶质母细胞瘤）演变而来的肿瘤。我们测定了445例中枢神经系统（CNS）肿瘤和494例非CNS肿瘤中IDH1基因和相关IDH2基因的序列。在用这些基因转染的培养的神经胶质瘤细胞中测定由正常和突变IDH1和IDH2基因产生的蛋白质的酶活性。我们在超过70%的WHO II级和III级星形细胞瘤和少突胶质细胞瘤以及从这些低级别病变发展而来的胶质母细胞瘤中确定了影响IDH1氨基酸132的突变。没有IDH1突变的肿瘤通常具有影响IDH2基因的类似氨基酸（R172）的突变。具有IDH1或IDH2突变的肿瘤具有独特的遗传和临床特征，患有此类肿瘤的患者比野生型IDH基因的患者具有更好的预后。四个测试的IDH1和IDH2突变中的每一个都降低了编码蛋白的酶活性。由IDH1和IDH2编码的NADP+依赖性异柠檬酸脱氢酶的突变发生在大多数几种类型的恶性胶质瘤中。
A recent genomewide mutational analysis of glioblastomas (World Health Organization [WHO] grade IV glioma) revealed somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such tumors, most frequently in tumors that were known to have evolved from lower-grade gliomas (secondary glioblastomas). We determined the sequence of the IDH1 gene and the related IDH2 gene in 445 central nervous system (CNS) tumors and 494 non-CNS tumors. The enzymatic activity of the proteins that were produced from normal and mutant IDH1 and IDH2 genes was determined in cultured glioma cells that were transfected with these genes. We identified mutations that affected amino acid 132 of IDH1 in more than 70% of WHO grade II and III astrocytomas and oligodendrogliomas and in glioblastomas that developed from these lower-grade lesions. Tumors without mutations in IDH1 often had mutations affecting the analogous amino acid (R172) of the IDH2 gene. Tumors with IDH1 or IDH2 mutations had distinctive genetic and clinical characteristics, and patients with such tumors had a better outcome than those with wild-type IDH genes. Each of four tested IDH1 and IDH2 mutations reduced the enzymatic activity of the encoded protein. Mutations of NADP+-dependent isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority of several types of malignant gliomas.