Lung adenocarcinoma (LUAD) is a common type of lung cancer with high incidence and poor prognosis. Hypoxia and DNA methylation play important regulatory roles in cancer progression. The purpose of this study was to explore the relationship between hypoxia and DNA methylation, and to identify key genes for hypoxia-regulated LUAD progression. Hypoxia score (HS) was calculated using the GSVA algorithm. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and protein–protein interaction (PPI) analysis were performed using clusterProfile package, STRING database and Cytoscape software. Kaplan-Meier curves of overall survival (OS) and disease-free survival (DFS) were drawn using R software. Smoking status and cancer stages were significantly associated with LUAD hypoxia, and hypoxia is a poor prognostic factor for LUAD. Compared with HS-low group, 1803 aberrantly methylated DEGs were identified in HS-high group. KEGG analysis showed that the 1803 genes were enriched in the metabolic pathways associated with hypoxia stress, angiogenesis, and cancer progression. FAM20C, MYLIP and COL7A1 were identified as the hypoxia-related key genes in LUAD progression, which were regulated by DNA methylation. Hypoxia in LUAD tumor cells led to changes in DNA methylation patterns. In-depth study of the relationship between hypoxia and DNA methylation is helpful to elucidate the mechanism of tumorigenesis, and provide new ideas for LUAD treatment.

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