Wang Z, Liu X, Wang Z, Bao Z, Zhang W, Zhang C, Jiang T
Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China.
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China.
Curr Mol Med. 2018 Mar 9;17(7):518-526. doi: 10.2174/1566524018666180212151429.
Isocitrate dehydrogenase (IDH) mutation is the initiating event that defines major clinical and prognostic classes of gliomas, but the potential mechanisms have not been well interpreted yet. The main objective of the current study was to better understand the underlying biology of IDH mutant gliomas as captured by gene expression profiles.
RNA sequencing data of WHO grade II-IV gliomas from the Chinese Glioma Genome Atlas (CGGA, N=325) were used to assess differentially expressed genes between IDH mutant and wild type gliomas and to construct a gene expression-based classifier to detect IDH mutant samples with high sensitivity and specificity. The classifier was validated in independent RNA sequencing data from the Cancer Genome Atlas (TCGA, N=699), and the prognostic value of the classifier was also assessed in the two datasets.
A 58-gene-pair IDH mutation signature was developed by using the top scoring pairs algorithm. In CGGA dataset, 98.5% and 100% IDH mutant samples were also predicted to be mutant by gene expression based IDH status in grade II-III and grade IV gliomas, respectively. In TCGA dataset, the proportions were 99.8% and 100%, respectively. The signature remained to be a prognostic marker in multivariate cox analysis both in CGGA and TCGA datasets.
A characteristic gene expression signature is associated with and accurately predicts IDH mutation status. This suggests a common biology between these tumors and adds prognostic and biologic information that is not captured by the mutation status alone. These results may help in population stratification for clinical trials. As RNA-seq is more and more prevalent and cost-effective in glioma molecular diagnosis, this gene signature would provide a precise method to predict IDH mutation status with RNA-seq data.
异柠檬酸脱氢酶（IDH）突变是定义胶质瘤主要临床和预后类别的起始事件，但其潜在机制尚未得到很好的解释。本研究的主要目的是通过基因表达谱更好地理解IDH突变型胶质瘤的潜在生物学特性。
使用来自中国胶质瘤基因组图谱（CGGA，N = 325）的WHO II-IV级胶质瘤的RNA测序数据，评估IDH突变型和野生型胶质瘤之间的差异表达基因，并构建基于基因表达的分类器，以高灵敏度和特异性检测IDH突变样本。该分类器在来自癌症基因组图谱（TCGA，N = 699）的独立RNA测序数据中进行了验证，并且还在这两个数据集中评估了该分类器的预后价值。
使用得分最高的基因对算法开发了一个包含58个基因对的IDH突变特征。在CGGA数据集中，II-III级和IV级胶质瘤中分别有98.5%和100%的IDH突变样本通过基于基因表达的IDH状态预测为突变型。在TCGA数据集中，这一比例分别为99.8%和100%。在CGGA和TCGA数据集中，该特征在多变量cox分析中仍然是一个预后标志物。
一种特征性的基因表达特征与IDH突变状态相关并能准确预测该状态。这表明这些肿瘤之间存在共同的生物学特性，并增加了仅由突变状态无法捕获的预后和生物学信息。这些结果可能有助于临床试验中的人群分层。由于RNA测序在胶质瘤分子诊断中越来越普遍且具有成本效益，这种基因特征将为利用RNA测序数据预测IDH突变状态提供一种精确的方法。
