Genome-scale meta-analysis of DNA methylation during progression of lung adenocarcinoma

Identification of epigenetic alterations in tumors has become a common method for identifying genes critical to cancer development and progression. Thus, we identified DNA methylation alterations on the genome scale during lung adenocarcinoma (LADC) progression to understand the carcinogenic process and identify clinically relevant biomarkers. We found that epigenetic alterations in LADC mainly occur during the early stage of LADC progression, and there are no significant methylation differences between early-stage and late-stage LADCs. This suggests that DNA methylation alterations characterize a turning point of early events in LADC progression. By comparing DNA methylation between early-stage LADCs and normal lung tissues, we further identified 940 genes with significant alterations in DNA methylation. Sixty-seven genes were found to exhibit strong correlation between methylation alterations and expression changes, based on associated gene expression data. According to gene ontology analysis, these genes are involved in lung development, respiratory system development, cell cycle, histidine metabolism, the Wnt signaling pathway, and the p53 signaling pathway. We also found that genes on chromosome 18 most frequently showed promoter hypermethylation. Moreover, we found that LADC-associated DNA hypomethylation occurred preferentially at neither histone H3 lysine 4 nor histone H3 lysine 27 mark domains in human embryonic stem cells (NMDs) and that hypomethylation of NMDs was associated with a poor prognostic signature in LADC. Our findings have important implications for LADC progression because of the identification of novel epigenetic biomarkers potentially involved in early-stage LADC and for establishing the importance of NMD DNA hypomethylation for predicting prognosis in LADC.