OBJECTIVES: Epigenetic alterations like methylation of tumor suppressor genes or oncogenes, in respiratory epithelium have been associated with lung cancer. Hypermethylation of genes promoter is an epigenetic event, and is responsible to tumor suppressor genes inactivation as well as oncogenes activation. This study aimed to assess the role of methylation status in promoter of and genes their potential implication in the pathogenesis of lung tumor in Iranian patients. METHODS: In this study, we collected 100 tissue samples (50 lung cancer tissues and 50 adjacent non-cancerous lung tissues) from Iranian lung cancer patients. The genomic DNA was extracted, and methylation status of both and  genes was investigated by methylation-sensitive high-resolution melting (MS-HRM) assay technique and Real-Time PCR. Cancer Genome Atlas (TCGA) dataset was also analyzed for further validation of the gene's methylation. RESULTS: Methylation of gene promoter was significantly higher in lung tumor tissues. However, promoter methylation levels of gene was significantly lower in lung tumor tissues. These results were additionally confirmed by TCGA analysis. Promoter methylation of both and genes was significantly associated with lymph node metastasis, and clinical stage of lung cancer. The receiver operating characteristic (ROC) curve analysis indicated a high accuracy of promoter methylation in these genes as a diagnostic biomarker for lung cancer. CONCLUSIONS: Methylation levels of both and genes promoters were associated with lung cancer pathogenesis in Iranian population, and may be a suitable biomarker for diagnosis and prognosis of lung cancer in early stage of tumorigenesis.