Promoter methylation of retinoic acid receptor beta 2 and the development of second primary lung cancers in non-small-cell lung cancer

Purpose: To investigate whether the promoter hypermethylation of retinoic acid receptor beta 2 (RARβ2) is associated with the development of second primary lung cancers (SPLCs) differentially according to smoking status in primary non-small-cell lung cancer (NSCLC). Patients and Methods: We retrospectively analyzed the relationship between RARβ2 methylation and the SPLC development in a total of 342 NSCLCs. The methylation status of RARβ2 was determined by using methylation-specific polymerase chain reaction. The difference in the time to SPLC development was analyzed by using the log-rank test and the Cox proportional hazards model. The median follow-up was 4.1 years. Results: SPLCs developed in 19 (5.6%) of the 342 NSCLCs, and overall incidence rate of SPLC development was 1.54 per 100 patient-years. SPLCs did not occur in 39 patients who had not smoked. After controlling for possible confounding factors, the hazard of failure for former smokers with RARβ2 hypermethylation was about 2.87 (95% CI, 0.92 to 13.64; P = .08) times higher compared to those without RARβ2 methylation. However, for current smokers, hypermethylation of the RARβ2 was found to have a protective effect against the SPLC development (hazard ratio = 0.23; 95% CI, 0.11 to 0.87; P = .03). Conclusion: Hypermethylation of RARβ2 promoter had a differential effect on the development of SPLCs in NSCLC, and this was dependent on smoking status. Our study suggests that a combination of retinoids and/or a demethylating agent may be effective in the prevention of SPLCs in never-smokers and former smokers with NSCLC.