Isocitrate Dehydrogenase 1/2 Mutational Analyses and 2-Hydroxyglutarate Measurements in Wilms Tumors
Isocitrate Dehydrogenase 1/2 Mutational Analyses and 2-Hydroxyglutarate Measurements in Wilms Tumors
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DOI：
10.1002/pbc.22697
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发表时间：
2011-03-01
影响因子：
3.2
通讯作者：
DeBerardinis, Ralph J.
中科院分区：
文献类型：
--
作者：
Rakheja, Dinesh;Mitui, Midori;DeBerardinis, Ralph J.
背景L-2-羟基葡萄糖酸尿症（L-2-HGA）是一种少见的先天性代谢异常，易发生脑肿瘤。已证实与编码NADP（+）依赖性异柠檬酸脱氢酶（分别为IDH 1和IDH 2）的基因体细胞突变相关的恶性胶质瘤和髓性白血病中D-2-羟基戊二酸水平升高。最近，我们注意到一个肾母细胞瘤的儿童与L-2-HGA。鉴于2-羟基戊二酸的两种对映体与细胞转化相关的证据越来越多，我们研究了散发性肾母细胞瘤是否与IDH 1或IDH 2突变或2-羟基戊二酸水平升高相关。Procedure.我们取出了21个冷冻的肾母细胞瘤组织。在20例病例中，我们对IDH 1和IDH 2的外显子4和侧翼内含子区进行了测序。在所有21例病例中，我们通过液相色谱-串联质谱法测量了2-羟基戊二酸水平。结果我们没有发现IDH 1密码子132或IDH 2密码子172的热点突变。2例病例（1例组织学良好，1例组织学不良）显示IDH 1中的杂合变化c.211G>A（p.Val71Ile），该变化先前报告为突变，但在NCBI SNP数据库中列为单核苷酸多态性。我们在任何样本中均未发现2-羟基谷氨酸水平升高。结论.我们的研究结果表明IDH 1密码子132或IDH 2密码子172突变或2-羟基戊二酸水平升高在散发性肾母细胞瘤的生物学中不起作用。在两个肿瘤中观察到的IDH 1中c.211G>A（p.Val71Ile）杂合变化的意义尚不清楚。儿科血液癌症2011;56：379-383。(C)2010 Wiley-Liss，Inc.
Background. L-2-Hydroxyglutaric aciduria (L-2-HGA) is an uncommon inborn error of metabolism, in which the patients are predisposed to develop brain tumors. Elevated levels of D-2-hydroxyglutarate have been demonstrated with malignant gliomas and myeloid leukemias associated with somatic mutations of the genes encoding NADP(+)-dependent isocitrate dehydrogenases (IDH1 and IDH2, respectively). Recently, we noted a Wilms tumor in a child with L-2-HGA. Given the accumulating evidence that both enantiomers of 2-hydroxyglutarate are associated with cellular transformation, we investigated if sporadic Wilms tumors are associated with IDH1 or IDH2 mutations or with elevated levels of 2-hydroxyglutarate. Procedure. We retrieved 21 frozen Wilms tumor tissues. In 20 cases, we sequenced exon 4 and flanking intronic regions of IDH1 and IDH2. In all 21 cases, we measured 2-hydroxyglutarate levels by liquid chromatography-tandem mass spectrometry. Results. We did not find mutations at the hot spots IDH1 codon 132 or IDH2 codon 172. Two cases (1 with favorable histology and 1 With unfavorable histology) showed heterozygous change c.211G>A (p.Val71Ile) in IDH1, a change previously reported as a mutation but listed as a single nucleotide polymorphism in the NCBI SNP database. We did not find increased levels of 2-hydroxygluatric acid in any sample. Conclusions. Our results suggest that IDH1 codon 132 or IDH2 codon 172 mutations or elevated 2-hydroxyglutarate levels do not play a role in the biology of sporadic Wilms tumors. The significance of heterozygous change c.211G>A (p.Val71Ile) in IDH1, seen in two tumors, is not clear. Pediatr Blood Cancer 2011;56:379-383. (C) 2010 Wiley-Liss, Inc.