Integrated analysis of gene expression and DNA methylation datasets identified key genes and a 6-gene prognostic signature for primary lung adenocarcinoma

Abstract Lung adenocarcinoma (LUAD) is the main subtype of non-small cell lung cancer with a poor survival prognosis. In our study, gene expression, DNA methylation, and clinicopathological data of primary LUAD were utilized to identify potential prognostic markers for LUAD, which were recruited from The Cancer Genome Atlas (TCGA) database. Univariate regression analysis showed that there were 21 methylation-associated DEGs related to overall survival (OS), including 9 down- and 12 up-regulated genes. The 12 up-regulated genes with hypomethylation may be risky genes, whereas the other 9 down-regulated genes with hypermethylation might be protective genes. By using the Step-wise multivariate Cox analysis, a methylation-associated 6-gene (consisting of CCL20, F2, GNPNAT1, NT5E, B3GALT2, and VSIG2) prognostic signature was constructed and the risk score based on this gene signature classified patients into high- or low-risk groups. Patients of the high-risk group had shorter OS than those of the low-risk group in both the training and validation cohort. Multivariate Cox analysis and the stratified analysis revealed that the risk score was an independent prognostic factor for LUAD patients. The methylation-associated gene signature may serve as a prognostic factor for LUAD patients and the represent hypermethylated or hypomethylated genes might be potential targets for LUAD therapy.

摘要：肺腺癌（LUAD）是非小细胞肺癌的主要亚型，患者生存预后较差。本研究从癌症基因组图谱（The Cancer Genome Atlas, TCGA）数据库中获取原发性肺腺癌的基因表达、DNA甲基化与临床病理数据，以筛选该疾病的潜在预后标志物。单因素回归分析显示，共存在21个与总生存期（overall survival, OS）相关的甲基化相关差异表达基因（differentially expressed genes, DEGs），其中9个为下调基因，12个为上调基因。这12个伴低甲基化的上调基因可能为风险基因，而其余9个伴高甲基化的下调基因则可能为保护基因。通过逐步多因素Cox回归分析，本研究构建了一套由CCL20、F2、GNPNAT1、NT5E、B3GALT2及VSIG2组成的甲基化相关6基因预后特征，并基于该基因特征计算风险评分，将患者划分为高风险组与低风险组。在训练队列与验证队列中，高风险组患者的总生存期均短于低风险组患者。多因素Cox回归分析与分层分析结果显示，风险评分是肺腺癌患者的独立预后因素。该甲基化相关基因特征可作为肺腺癌患者的预后标志物，其中的高甲基化或低甲基化基因或可成为肺腺癌治疗的潜在靶点。