RARβ2 hypermethylation is associated with poor recurrence-free survival in never-smokers with adenocarcinoma of the lung

• Published in: Clinical epigenetics Vol. 7; no. 1; p. 32
• Main Authors: Kim, Yujin, Jin, DongHao, Lee, Bo Bin, Cho, Eun Yoon, Han, Joungho, Shim, Young Mog, Kim, Duk-Hwan
• Format: Journal Article
• Language: English
• Published: Germany BioMed Central 19.03.2015
• Subjects: Never-smoker; RARβ2; Recurrence; Methylation; Lung cancer
• ISSN: 1868-7075; 1868-7083
• DOI: 10.1186/s13148-015-0066-4

This study was aimed at investigating if the effect of RARβ2 hypermethylation on recurrence-free survival (RFS) in non-small cell lung cancer (NSCLC) depends on one's smoking status and specific interacting proteins. We retrospectively analyzed the expressions of five proteins using immunohistochemistry in archival formalin-fixed and paraffin-embedded tissues from 578 NSCLC patients who had undergone surgical resection from 1994 through 2004. Promoter methylation of RARβ2 was assessed by bisulfite pyrosequencing. Recurrence was found in 268 (46%) of 578 NSCLCs with a median follow-up period of 4.8 years. Overexpression of β-catenin, c-MET, cyclin D1, and EGFR occurred in 55%, 72%, 51%, and 41% of the patients, respectively. E-cadherin expression was negative in 62% of the patients, and RARβ2 hypermethylation was found in 37%. The abnormal expression of c-MET (P = 0.002) and EGFR (P = 0.001) was found to be highly prevalent in never-smokers. RARβ2 hypermethylation was significantly associated with poor recurrence-free survival (RFS) in 128 never-smokers with adenocarcinoma (P = 0.01) For parsimonious model building, the five proteins were clustered into three groups (β-catenin and E-cadherin; c-MET; cyclin D1 and EGFR) by an unsupervised hierarchical clustering and were included in a multivariate analysis. Cox proportional hazard analysis showed that RARβ2 hypermethylation was significantly associated with poor RFS in 128 never-smokers with adenocarcinoma (adjusted hazard ratio [HR] = 2.19, 95% confidence interval [CI] = 1.28 to 3.47; P = 0.009), after adjusting for interacting proteins. The present study suggests that RARβ2 hypermethylation may be an independent prognostic factor of RFS in never-smokers with adenocarcinoma of the lung.