Genome-wide analysis of methylation CpG sites in gene promoters identified four pairs of CpGs-mRNAs associated with lung adenocarcinoma prognosis.

Abstract Background Activation of oncogenes through promoter hypomethylation and silencing of tumor suppressor genes induced by promoter hypermethylation played essential roles in the progression of lung adenocarcinoma (LUAD). This study aimed to identify the LUAD prognostic CpG sites and the regulated genes which contributed to LUAD progression. Methods Methylation profiles from TCGA and GSE60645 were used to screen the differentially methylated CpGs. Then, the Log-rank test was adopted to identify LUAD prognosis-associated CpGs. Differential gene expression and survival analyses were further performed to suggest the roles of methylation-driven genes in LUAD prognosis. Finally, models and nomograms were constructed to predict the prognosis of LUAD. Results A total of 1,891 CpGs at gene promoters were differentially methylated. Among them, 54 CpGs were significantly associated with LUAD prognosis. Nine of them showed significant correlations with the expression of four genes (CCDC181, CFTR, PPP1R16B, MYEOV). CCDC181, CFTR and PPP1R16B were aberrantly down-regulated in LUAD, while MYEOV was up-regulated. All of them were significantly associated with LUAD prognosis. The LASSO regression analysis indicated that tumor stages, cg09181792, cg16998150, cg22779330 and PPP1R16B were promising prognostic factors. The AUC (area under the curve) of the model containing the clinical predictors was 0.643. The combination of CpGs and PPP1R16B with clinical variables significantly improved the predictive efficiency with an AUC of 0.714 (P = 0.036). Conclusion This study identified four pairs of promoter CpGs and genes that were significantly associated with LUAD prognosis. The integration of CpGs methylation and gene expression showed better predictive ability for LUAD prognosis.