PDF(Pubmed)
Abstract：
Mutations affecting codon 172 of the isocitrate dehydrogenase 2 (IDH2) gene define a subgroup of sinonasal undifferentiated carcinomas (SNUCs) with a relatively favorable prognosis and a globally hypermethylated phenotype. They are also recurrent (along with IDH1 mutations) in gliomas, acute myeloid leukemia, and intrahepatic cholangiocarcinoma. Commonly reported mutations, all associated with aberrant IDH2 enzymatic activity, include R172K, R172S, R172T, R172G, and R172M. We present a case of SNUC with a never-before-described IDH2 mutation, R172A. Our report compares the methylation pattern of our sample to other cases from the Gene Expression Omnibus database. Hierarchical clustering suggests a strong association between our sample and other IDH-mutant SNUCs and a clear distinction between sinonasal normal tissues and tumors. Principal component analysis (PCA), using 100 principal components explaining 94.5% of the variance, showed the position of our sample to be within 1.02 standard deviation of the other IDH-mutant SNUCs. A molecular modeling analysis of the IDH2 R172A versus other R172 variants provides a structural explanation to how they affect the protein active site. Our findings thus suggest that the R172A mutation in IDH2 confers a gain of function similar to other R172 mutations in IDH2, resulting in a similar hypermethylated profile.
摘要：
影响异柠檬酸脱氢酶2（IDH2）基因的密码子172的突变定义了鼻窦未分化癌（SNUCs）的一个亚组，具有相对良好的预后和全球高甲基化表型。它们也在神经胶质瘤中复发（连同IDH1突变），急性髓系白血病,和肝内胆管癌。通常报道的突变，所有这些都与异常的IDH2酶活性有关，包括R172K，R172S,R172T,R172G,和R172M。我们介绍了一个SNUC的病例，该病例具有从未描述过的IDH2突变，R172A.我们的报告将我们样本的甲基化模式与来自基因表达综合数据库的其他病例进行了比较。分层聚类表明我们的样品与其他IDH突变体SNUCs之间存在很强的关联，并且在鼻窦正常组织和肿瘤之间存在明显的区别。主成分分析(PCA)，使用100个主成分解释94.5%的方差，显示我们样品的位置在其他IDH突变体SNUC的1.02标准偏差内。IDH2R172A与其他R172变体的分子建模分析提供了它们如何影响蛋白质活性位点的结构解释。因此，我们的发现表明，IDH2中的R172A突变赋予了与IDH2中其他R172突变相似的功能，从而产生了相似的高甲基化谱。
