RASSF1A is not appropriate as an early detection marker or a prognostic marker for non-small cell lung cancer

Aberrant methylation of several tumor suppressor genes often occurs during the pathogenesis of lung cancer. RASSF1A is one of the tumor suppressor genes, and it is frequently inactivated by hypermethylation of its promoter region in a variety of human cancers, including lung cancer. It has recently been suggested that RASSF1A methylation was frequently observed in poorly differentiated tumors, and that it was correlated with adverse survival in lung adenocarcinoma (Tomizawa Y, et al., Clin Cancer Res 2002;8:2362-8). In this study, we investigated the pathogenetic and clinicopathologic significance of RASSF1A methylation for the development and/or progression of non small cell lung cancer (NSCLC). We examined 116 cases of NSCLC for the methylation status of RASSF1A. Methylation-specific analysis demonstrated that 40.5% (47 of 116) of the cases were methylated at the CpG sites in the promoter. Methylation of RASSF1A was associated with cellular differentiation (p = 0.0244) and it was related to survival (p = 0.0276). However, there was no association between RASSF1A methylation and the individual clinicopathologic features: TNM stage (p > 0.1), recurrence (p > 0.1), lymphatic permeation (p > 0.1) and smoking duration time (p > 0.1). Furthermore, we analyzed RASSF1A's probability as a prognostic marker by using stepwise Cox proportional hazard regression testing. As a result, the stage proved to be the most important factor (p = 0.0089), more than any other factors such as age, gender, cell type, methylation status, differentiation, smoking duration time, tumor size and lymph node permeation. There was no other significant factor other than stage and age. These results show that epigenetic inactivation of RASSF1A cannot be a prognostic marker of NSCLC.