Multiple regression identified stage-associated hazardous factors.<h4>Results</h4>In our cohort, Shox2 and Rassf1a methylation were correlated with more aggressive clinicopathological characteristics (age, sex, smoking, drinking, TNM stage and histological progression) and exhibited significant diagnostic potential for distinguishing early-stage lesions (adenocarcinoma <i>in situ</i> from LUAD across stages I-IV) and histological progression (minimally invasive adenocarcinoma versus invasive adenocarcinoma). Here, SHOX2 is linked to adenocarcinoma.