Comprehensive Analysis of DNA Methylation and Gene Expression Datasets Identified MMP9 and TWIST1 as Important Pathogenic Genes of Lung Adenocarcinoma

DNA Cell Biol. 2018 Apr;37(4):336-346. doi: 10.1089/dna.2017.4085. Epub 2018 Feb 14.


Due to the high mortality of lung cancer, early diagnosis followed by early effective treatment is the key to prognosis improvement, which demands to identify the biological targets. Therefore, a multistage screening analysis was used to identify biological targets of lung adenocarcinoma. Two independent datasets of DNA methylation and RNA expression microarray in lung adenocarcinoma and normal lung tissues were chosen from the Gene Expression Omnibus. The association between DNA methylation and gene expression was explored, and the prognostic value of the hub genes was also evaluated. In this study, 8533 differential methylation sites, mostly located in the CpG island region and corresponding to 2754 genes (referred as differential methylation genes), were detected from methylation microarray. Besides, we obtained 830 differential expression genes, including 570 downregulated and 260 upregulated genes, through differential expression analysis. Protein-protein interaction analysis identified CXCL12, GFR, KDR, MMP9, TEK, and TWIST as core nodes, involving in the process of tumor cell identification, cell growth, cytokine secretion, inflammatory response, and angiogenesis. Among them, MMP9 and TWIST1 were identified as more valuable biological targets for the early diagnosis and targeted therapy of lung cancer through Kaplan-Meier analysis of TCGA lung adenocarcinoma datasets. Our study should contribute to the diagnosis and treatment of lung adenocarcinoma.

Keywords: DNA methylation; GEO; gene expression; lung adenocarcinoma.

MeSH terms

  • Adenocarcinoma / diagnosis
  • Adenocarcinoma / genetics*
  • Adenocarcinoma of Lung
  • Biomarkers, Tumor / genetics
  • CpG Islands
  • DNA Methylation*
  • Gene Expression Profiling / methods
  • Humans
  • Kaplan-Meier Estimate
  • Lung Neoplasms / diagnosis
  • Lung Neoplasms / genetics*
  • Matrix Metalloproteinase 9 / genetics*
  • Matrix Metalloproteinase 9 / metabolism
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Prognosis
  • Transcriptome
  • Twist-Related Protein 1 / genetics*
  • Twist-Related Protein 1 / metabolism


  • Biomarkers, Tumor
  • Nuclear Proteins
  • TWIST1 protein, human
  • Twist-Related Protein 1
  • MMP9 protein, human
  • Matrix Metalloproteinase 9