Clear cell renal cell carcinoma (ccRCC) is the most prevalent renal malignancy in adults with generally poor prognosis. This study aimed to establish a DNA methylation-driven gene-based prognostic model for ccRCC. We collected DNA methylation and gene expression profiles of over 1500 ccRCC samples from The Cancer Genome Atlas (TCGA) dataset, four Gene Expression Omnibus (GEO) datasets, the Genotype-Tissue Expression (GTEx) dataset, and cancer cell lines from Cancer Cell Line Encyclopedia database and performed comprehensive bioinformatics analysis. As a result, a total of 31 differentially expressed methylation-driven genes (DEMDGs) were identified. After univariate Cox regression, least absolute shrinkage and selection operator, and multivariate Cox regression analyses, four (NFE2L3, HHLA2, IFI16, and ZNF582) were finally selected to construct a risk score prognostic model. The high-risk group demonstrated significantly poor prognosis than the low-risk group did in TCGA training (hazard ratio [HR] = 3.533, p < 0.001), TCGA internal, and GEO external validation datasets. Furthermore, the nomogram, including the prognostic model and clinical factors, showed promising prognostic value (HR = 5.756, p < 0.001, and area under the curve at 1 year = 0.856). In addition, the model was found to be significantly associated with drug sensitivity of eight targeted agents. These findings provided a novel and reliable four DEMDG-based prognostic model for ccRCC.

中文翻译：

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识别和全面验证基于DNA甲基化驱动基因的透明细胞肾细胞癌预后模型。

透明细胞肾细胞癌（ccRCC）是预后普遍较差的成年人中最普遍的肾恶性肿瘤。这项研究旨在建立ccRCC的DNA甲基化驱动的基于基因的预后模型。我们从癌症基因组图谱（TCGA）数据集，四个基因表达综合（GEO）数据集，基因型组织表达（GTEx）数据集和癌症细胞系的癌细胞系中收集了1500多个ccRCC样本的DNA甲基化和基因表达谱百科全书数据库并进行了全面的生物信息学分析。结果，总共鉴定出31个差异表达的甲基化驱动基因（DEMDGs）。在单变量Cox回归，最小绝对收缩和选择算子以及多元Cox回归分析之后，有四个（NFE2L3，HHLA2，IFI16和ZNF582）的最终选择，构建风险评分预后模型。在TCGA培训（风险比[HR] = 3.533，p  <0.001），TCGA内部和GEO外部验证数据集中，高风险组的预后明显低于低风险组。此外，列线图，包括预后模型和临床因素，显示出有希望的预后价值（HR = 5.756，p  <0.001，曲线下面积1年= 0.856）。此外，发现该模型与八种靶向药物的药物敏感性显着相关。这些发现为ccRCC提供了一种新颖可靠的基于DEMDG的四个预后模型。