Abstract
PurposeThe exploration and interpretation of DNA methylation-driven genes might contribute to molecular classification, prognostic prediction and therapeutic choice. In this study, we built a prognostic risk model via integrating analysis of the transcriptome and methylation profile for patients with gastric cancer (GC).MethodsThe mRNA expression profiles, DNA methylation profiles and corresponding clinicopathological information of 415 GC patients were downloaded from The Cancer Genome Atlas (TCGA). Differential expression and correlation analysis were performed to identify DNA methylation-driven genes. The candidate genes were selected by univariate Cox regression analyses followed by the least absolute shrinkage and selection operator (LASSO) regression. A prognostic risk nomogram model was then built together with clinicopathological parameters.Results5 DNA methylation-driven genes (CXCL3, F5, GNAI1, GAMT and GHR) were identified by integrated analyses and selected to construct the prognostic risk model with clinicopathological parameters. High expression and low DNA hypermethylation of F5, GNAI1, GAMT and GHR, as well as low expression and high DNA hypomethylation of CXCL3 were significantly associated with poor prognosis rates, respectively. The high-risk group showed a significantly shorter prognosis than the low-risk group in the TCGA dataset (HR = 0.212, 95% CI = 0.139–0.322, P = 2e-15). The final nomogram model showed high predictive efficiency and consistency in the training and validation group.ConclusionWe construct and validate a prognostic nomogram model for GC based on five DNA methylation-driven genes with high performance and stability. This nomogram model might be a powerful tool for prognosis evaluation in the clinic and also provided novel insights into the epigenetics in GC.
Highlights
Gastric cancer (GC) is the third leading cause of cancer-related death and the fifth most common cancer worldwide [1]
In the era of precision medicine, omics analysis based on DNA, RNA and protein of GC tissues have revealed molecular classifications associated with diagnosis and prognosis [3,4,5]
Various cancers were characterized with the aberrant DNA methylation, such as hypomethylation of oncogene and hypermethylation of suppressor gene, which was involved in tumorigenesis, heterogeneity and therapeutic resistance [8]
Summary
Gastric cancer (GC) is the third leading cause of cancer-related death and the fifth most common cancer worldwide [1]. Diagnostic and prognostic models based on molecular signature and clinical features of patients with GC have important practical value. The exploration and interpretation of DNA methylation-driven genes might contribute to molecular classification, prognostic prediction, and therapeutic choice. The prognostic value of MGMT promoter methylation in patients with high-risk glioma treated with radiotherapy and temozolomide highlighted the application feasibility of DNA methylation in clinical implementation [9]. In patients with GC, previous studies have revealed that DNA methylation could serve as molecular biomarkers in helicobacter pylori infection, cancer occurrence, and prognosis [10]. The molecular mechanisms underlying gene-expression regulated by DNA methylation is unclear, and the diagnostic and prognostic value of these DNA methylation-driven gene remains to be future explored
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