Hypermethylation of normal mucosa of esophagus-specific 1 is associated with an unfavorable prognosis in patients with non-small cell lung cancer

Lung cancer is the leading cause of cancer-associated mortality due to high incidence and poor survival rates, irrespective of global variations in its biology and treatment. Changes in DNA methylation are frequent in cancer and constitute an important mechanism in tumorigenesis. Normal mucosa of esophagus-specific 1 (NMES1) is expressed in epithelial tissue and is believed to be a tumor suppressor gene. The present study investigated the methylation status of the NMES1 promoter in 178 cases of primary non-small cell lung cancer (NSCLC) by pyrosequencing and evaluated the prognostic value of this methylation. NMES1 methylation-positive tumors above the background threshold for non-malignant tissue were found in 15 cases (8.4%) and were detected exclusively in malignant tissues. In addition, univariate and multivariate analyses showed that methylation-positive patients experienced worse overall survival rate (OSR) compared with methylation-negative patients (adjusted hazard ratio, 2.62; 95% confidence interval, 1.20-5.69; P=0.02). Notably, within the methylation-positive group, patients with strong methylation tended to experience worse OSR compared with those with weak methylation (adjusted hazard ratio, 2.45 vs. 3.05; P_trend=0.02). These findings suggest that NMES1 may serve an important role in lung cancer pathogenesis, and its methylation could be considered a prognostic marker for NSCLC. Further studies with large numbers of samples are required to confirm this conclusion.