Xu Liexi, Huang Zhengrong, Zeng Zihang, Li Jiali, Xie Hongxin, Xie Conghua
Department of Radiation and Medical Oncology, Wuhan University of Zhongnan Hospital, Wuhan, China.
Tumor Precision Diagnosis and Treatment Technology and Translational Medicine, Hubei Engineering Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
Front Genet. 2022 Aug 29;13:970507. doi: 10.3389/fgene.2022.970507. eCollection 2022.
Abnormal DNA methylation of gene promoters is an important feature in lung adenocarcinoma (LUAD). However, the prognostic value of DNA methylation remains to be further explored. We sought to explore DNA methylation characteristics and develop a quantifiable criterion related to DNA methylation to improve survival prediction for LUAD patients. Illumina Human Methylation450K array data, level 3 RNA-seq data and corresponding clinical information were obtained from TCGA. Cox regression analysis and the Akaike information criterion were used to construct the best-prognosis methylation signature. Receiver operating characteristic curve analysis was used to validate the prognostic ability of the DNA methylation-related feature score. qPCR was used to measure the transcription levels of the identified genes upon methylation. We identified a set of DNA methylation features composed of 11 genes (, , , , , , , , , and ). The feature score, calculated based on DNA methylation features, was independent of tumor recurrence and TNM stage in predicting overall survival. Of note, the combination of this feature score and TNM stage provided a better overall survival prediction than either of them individually. The transcription levels of all the hypermethylated genes were significantly increased after demethylation, and the expression levels of 3 hypomethylated proteins were significantly higher in tumor tissues than in normal tissues, as indicated by immunohistochemistry data from the Human Protein Atlas. Our results suggested that these identified genes with prognostic features were regulated by DNA methylation of their promoters. Our studies demonstrated the potential application of DNA methylation markers in the prognosis of LUAD.
基因启动子的异常DNA甲基化是肺腺癌（LUAD）的一个重要特征。然而，DNA甲基化的预后价值仍有待进一步探索。我们试图探索DNA甲基化特征，并制定与DNA甲基化相关的可量化标准，以改善LUAD患者的生存预测。从TCGA获得了Illumina Human Methylation450K芯片数据、3级RNA测序数据及相应的临床信息。采用Cox回归分析和赤池信息准则构建最佳预后甲基化特征。采用受试者工作特征曲线分析来验证DNA甲基化相关特征评分的预后能力。使用qPCR来测量甲基化后所鉴定基因的转录水平。我们鉴定出一组由11个基因（、、、、、、、、、和）组成的DNA甲基化特征。基于DNA甲基化特征计算出的特征评分在预测总生存期时独立于肿瘤复发和TNM分期。值得注意的是，该特征评分与TNM分期相结合比单独使用它们中的任何一个能提供更好的总生存期预测。所有高甲基化基因的转录水平在去甲基化后显著增加，并且根据人类蛋白质图谱的免疫组化数据，3个低甲基化蛋白在肿瘤组织中的表达水平显著高于正常组织。我们的结果表明，这些具有预后特征的鉴定基因受其启动子DNA甲基化的调控。我们的研究证明了DNA甲基化标志物在LUAD预后中的潜在应用。
