Analysis at the single-cell level indicates an important role of heterogeneous global DNA methylation status on the progression of lung adenocarcinoma.

Aberrant DNA modifications affect the tumorigenesis and progression of lung cancer. However, the global methylation status of tumor cells and the heterogeneous methylation status of cells within the same tumor need further study. We used publicly available single-cell RNAseq data to investigate the impact and diversity of global methylation status on lung adenocarcinoma. Clustering cells into subgroups and cell differentiation pseudotime analysis, based on expression profile, demonstrated that the global methylation status was crucial to lung adenocarcinoma function and progression. Hypermethylated tumor cells had increased activity related to the hypoxia response. Hyper- and hypomethylated cells indicated upregulation in pathways involving focal adhesion and cell junctions. Pseudotime analysis showed that cell clusters with unique methylation activities were located at the ends of the putative trajectories, suggesting that DNA methylation and demethylation activities were essential to tumor cell progression. Expression of SPP1 was associated with the global methylation status of tumor cells and with patient prognosis. Our study identified the importance and diversity of global DNA methylation status by analysis at the single-cell level. Our findings provide new information about the global DNA methylation status of tumor cells and suggest new approaches for precision medical treatments for lung adenocarcinoma.