The prognostic value of RASSF1A promoter hypermethylation in non-small cell lung carcinoma: a systematic review and meta-analysis.

Inactivation of the tumor suppressor gene RASSF1A through methylation of the CpG islands within its promoter region as a prognostic factor for survival in non-small cell lung carcinoma (NSCLC) remains controversial. A meta-analysis of published studies investigating the effects of RASSF1A methylation on both relapse-free survival (RFS) and overall survival (OS) among NSCLC patients was performed. A total of 2802 patients from 19 eligible studies were included in the systematic review and 17 studies were included in the meta-analysis. In all, 32.6% of NSCLC patients had the methylated RASSF1A allele. Four of these studies investigated the correlation between RASSF1A methylation and RFS using univariate analysis. The univariate estimate for RFS was 1.87 [95% confidence interval (CI): 1.41-2.49; P < 0.0001] with no evidence of significant heterogeneity. Thirteen studies undertook univariate analyses of RASSF1A methylation and OS and 12 undertook multivariate analyses of RASSF1A methylation and OS. The pooled hazard ratio (HR) estimate for OS was 1.52 (95% CI: 1.33-1.74; P < 0.0001) by univariate analysis and 1.34 (95% CI: 1.15-1.57; P < 0.0001) by multivariate analysis. No significant heterogeneity was detected. For stages I-II NSCLC, the meta-risk remained highly significant by both univariate (HR = 1.94; 95% CI: 1.54-2.44; P < 0.0001) and multivariate analysis (HR = 1.39; 95% CI: 1.02-1.90; P = 0.039). This study shows that RASSF1A methylation appears to be an independent prognostic factor for poor survival in surgically treated NSCLC. However, the present findings require confirmation though adequately designed prospective studies.