title: RARβ2 hypermethylation is associated with poor recurrence-free survival in never-smokers with adenocarcinoma of the lung.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  The present study suggests that RARβ2 hypermethylation may be an independent prognostic factor of RFS in never-smokers with adenocarcinoma of the lung.
authors: Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, #300 Chunchun-dong, Jangan-Ku, Kyunggido, Suwon 440-746 South Korea.
authors: Yujin
authors: Y
authors: Kim
authors: Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, #300 Chunchun-dong, Jangan-Ku, Kyunggido, Suwon 440-746 South Korea.
authors: DongHao
authors: D
authors: Jin
authors: Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, #300 Chunchun-dong, Jangan-Ku, Kyunggido, Suwon 440-746 South Korea.
authors: Bo Bin
authors: BB
authors: Lee
authors: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, #50 Ilwon-dong, Kangnam-Ku, Seoul 135-710 South Korea.
authors: Eun Yoon
authors: EY
authors: Cho
authors: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, #50 Ilwon-dong, Kangnam-Ku, Seoul 135-710 South Korea.
authors: Joungho
authors: J
authors: Han
authors: Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, #50 Ilwon-dong, Kangnam-Ku, Seoul 135-710 South Korea.
authors: Young Mog
authors: YM
authors: Shim
authors: Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, #300 Chunchun-dong, Jangan-Ku, Kyunggido, Suwon 440-746 South Korea.|Samsung Biomedical Research Institute, Rm B155, #50 Ilwon-dong, Kangnam-Ku, Seoul 135-710 South Korea.
authors: Duk-Hwan
authors: DH
authors: Kim
keywords: Lung cancer; Methylation; Never-smoker; RARβ2; Recurrence