Chen Guang, Wang Yihan, Wang Lu, Xu Wanhai
Department of Urology, The 4th Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
Oncotarget. 2017 Jan 17;8(3):5268-5280. doi: 10.18632/oncotarget.14134.
The outcome of kidney renal clear cell carcinoma (KIRC) differs even among individuals with similar clinical characteristics. DNA methylation is regarded as a regulator of gene expression in cancers, which may be a molecular marker of prognosis. In this study, we aimed to mine novel methylation markers of the prognosis of KIRC. We revealed a total of 2793 genes differentially methylated in their promoter regions (DMGs) and 2979 differentially expressed genes (DEGs) in KIRC tissues compared with normal tissues using The Cancer Genome Atlas datasets. Then, we detected 57 and 34 subpathways enriched among the DMGs and DEGs, respectively, using the R package iSubpathwayMiner. We retained 56 subpathways related to both aberrant methylation and expression based on a hypergeometric test for further analysis. An integrated gene regulatory network was constructed using the regulatory relationships between genes in the subpathways. Using the top 15% of the nodes from the network ranked by degree, survival analysis was performed. We validated four DNA methylation signatures (RAC2, PLCB2, VAV1, and PARVG) as being highly correlated with prognosis in KIRC. These findings suggest that DNA methylation might become a prognostic predictor in KIRC and could supplement histological prognostic prediction.
肾透明细胞癌（KIRC）的预后即使在具有相似临床特征的个体之间也存在差异。DNA甲基化被认为是癌症中基因表达的调节因子，可能是一种预后的分子标志物。在本研究中，我们旨在挖掘KIRC预后的新型甲基化标志物。使用癌症基因组图谱数据集，我们发现与正常组织相比，KIRC组织中共有2793个基因在其启动子区域存在差异甲基化（差异甲基化基因，DMGs），以及2979个差异表达基因（DEGs）。然后，我们使用R包iSubpathwayMiner分别检测了DMGs和DEGs中富集的57个和34个亚通路。基于超几何检验，我们保留了56个与异常甲基化和表达均相关的亚通路用于进一步分析。利用亚通路中基因之间的调控关系构建了一个综合基因调控网络。使用网络中度排名前15%的节点进行生存分析。我们验证了四个DNA甲基化特征（RAC2、PLCB2、VAV1和PARVG）与KIRC的预后高度相关。这些发现表明，DNA甲基化可能成为KIRC的预后预测指标，并可补充组织学预后预测。
