Identification and functional characterization of isocitrate dehydrogenase 1 (IDH1) mutations in thyroid cancer.
Identification and functional characterization of isocitrate dehydrogenase 1 (IDH1) mutations in thyroid cancer.
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DOI：
10.1016/j.bbrc.2010.02.095
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发表时间：
2010-03-12
影响因子：
3.1
通讯作者：
Xing, Mingzhao
中科院分区：
文献类型：
--
作者：
Murugan, Avaniyapuram Kannan;Bojdani, Ermal;Xing, Mingzhao
关键词：
异柠檬酸脱氢酶1（IDH 1）和异柠檬酸脱氢酶2（IDH 2）的基因突变最近已被确定在胶质母细胞瘤。在本研究中，我们研究了甲状腺滤泡癌（FTC）和甲状腺间变性癌（ATC）中的IDH 1和IDH 2突变，后者与胶质母细胞瘤一样，具有快速侵袭性和致命性的临床过程。通过直接基因组DNA测序，我们分析了IDH 1和IDH 2基因的外显子4，这两个基因在胶质母细胞瘤中的突变热点密码子132和172分别在12个甲状腺癌细胞系，20个FTC和18个ATC肿瘤样品中。在ATC病例中发现了一种新型纯合G367 A IDH 1突变，导致密码子123处的G123 R氨基酸发生变化。先前描述的IDH 1 V71 I突变在FTC和ATC的情况下被发现，在细胞系中没有发现突变。因此，突变的总体患病率在FTC中为1/20（5%），在ATC中为2/18（11%）。我们在这些甲状腺癌细胞系和肿瘤样品中未发现IDH 2基因突变。16个物种的序列比对分析表明，新的IDH 1 G123 R突变位于一个高度保守的区域，提高了一个严重的功能后果的可能性，也可以预测从这个突变的正电荷氨基酸的发生。为了测试这一点，我们通过定点诱变产生了G123 R突变体，并证明IDH 1的酶活性降低，类似于作为对照测量的先前描述的R132 H IDH 1突变体的酶活性的预期降低。因此，功能相关的IDH 1突变也可以发生在甲状腺癌，特别是ATC，这表明IDH 1系统的潜在致瘤作用，可以代表甲状腺癌的新的治疗靶点。
Mutations in the genes for isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) have been recently identified in glioblastoma. In the present study, we investigated IDH1 and IDH2 mutations in follicular thyroid cancer (FTC) and anaplastic thyroid cancer (ATC), with the latter, like glioblastoma, having a rapidly aggressive and lethal clinical course. By direct genomic DNA sequencing, we analyzed exon 4 of the IDH1 and IDH2 genes that harbored the mutation hot spots codon 132 and 172 of the two genes in glioblastoma, respectively, in 12 thyroid cancer cell lines, 20 FTC and 18 ATC tumor samples. A novel homozygous G367A IDH1 mutation, resulting in a G123R amino acid change in codon 123, was identified in a case of ATC. A previously described IDH1 V71I mutation was found in a case of FTC and a case of ATC and no mutations were found in the cell lines. The overall prevalence of mutations was thus 1/20 (5%) in FTC and 2/18 (11%) in ATC. We did not find mutation in the IDH2 gene in these thyroid cancer cell lines and tumor samples. Sequence alignment analysis of 16 species revealed that the novel IDH1 G123R mutation was located in a highly conserved region, raising the possibility of a serious functional consequence as could also be predicted by the occurrence of a positively charged amino acid from this mutation. To test this, we created a G123R mutant by site-directed mutagenesis and demonstrated a decreased enzymatic activity of IDH1, similar to the expected reduction in the enzymatic activity of the previously described R132H IDH1 mutant measured as a control. Thus, functionally relevant IDH1 mutations can also occur in thyroid cancer, particularly ATC, suggesting a potential tumorigenic role of the IDH1 system that could represent a new therapeutic target for thyroid cancer.
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DOI：
10.1126/science.1170944
发表时间：
2009-04-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Zhao S;Lin Y;Xu W;Jiang W;Zha Z;Wang P;Yu W;Li Z;Gong L;Peng Y;Ding J;Lei Q;Guan KL;Xiong Y
通讯作者：
Xiong Y
DOI：
10.1126/science.1164382
发表时间：
2008-09-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Parsons DW;Jones S;Zhang X;Lin JC;Leary RJ;Angenendt P;Mankoo P;Carter H;Siu IM;Gallia GL;Olivi A;McLendon R;Rasheed BA;Keir S;Nikolskaya T;Nikolsky Y;Busam DA;Tekleab H;Diaz LA Jr;Hartigan J;Smith DR;Strausberg RL;Marie SK;Shinjo SM;Yan H;Riggins GJ;Bigner DD;Karchin R;Papadopoulos N;Parmigiani G;Vogelstein B;Velculescu VE;Kinzler KW
通讯作者：
Kinzler KW
影响因子：
15.9
作者：
Ichimura K;Pearson DM;Kocialkowski S;Bäcklund LM;Chan R;Jones DT;Collins VP
通讯作者：
Collins VP
影响因子：
4.8
作者：
Geisbrecht, BV;Gould, SJ
通讯作者：
Gould, SJ
影响因子：
2.9
作者：
Jennings, GT;Minard, KI;McAlisterHenn, L
通讯作者：
McAlisterHenn, L