Implication of p16INK4a and RASSF1A promoter methylation in patients with resectable non-small cell lung cancer (NSCLC)

Abstract

7150 Background::p16INK4a and RASSF1A are frequently inactivated by de novo PM in NSCLC. The goal of this study was to determine the prognostic roles of p16INK4a and RASSF1A PM in patients with resectable NSCLC Methods: status of p16INK4a and RASSF1A was determined in 119 tumors from patients with NSCLC (70 stage I/II and 49 stage IIIA) using methylation-specific PCR. Survival was estimated with the Kaplan-Meier method. Associations between methylation status and survival were determined by the log-rank test and Cox proportional hazards analysis Results: PM of p16INK4a and RASSF1A was detected in 58 (49%) and 46 (39%) tumors, respectively. Thirty-six (30%) tumors exhibited PM of both genes. In patients with stage I/II tumors, p16INK4a PM was strongly associated with poor overall, disease-free, and disease-specific survival (P = 0.002, P = 0.0006, and P = 0.0005, respectively, log-rank test) while the association between RASSF1A PM and survival was not significant. However, RASSF1A PM was a strong predictor of poor survival in patients with stage IIIA NSCLC (P< 0.0001, P = 0.0006, P< 0.0001, for overall, disease-free, and disease-specific survival, respectively). p16INK4a and RASSF1A PM were the only independent predictors of survival in multivariate analysis, and PM of both genes was associated with strikingly poor clinical outcome. In patients with stage IIIA tumors, all 11 patients in this category died of disease within 3 years after surgery, while 13 of 21 patients whose tumors had PM at only one gene died in 5 years, and 5 of 17 patients whose tumors had no PM died in 6.5 years ( P< 0.0001, log-rank test) Conclusions::p16INK4a and RASSF1A PM may be useful prognostic biomarkers for patients with resectable NSCLC. Stage IIIa patients whose tumors exhibited PM of both genes demonstrated significantly worse survival. Because these patients often receive adjuvant therapies, it would be worthwhile to examine relationships between PM status and response to therapy. No significant financial relationships to disclose.