Originally published as JCO Early Release 10.1200/JCO.2004.11.135 on July 26 2004

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kim, J. S. Articles by Kim, D.-H. Search for Related Content PubMed PubMed Citation Articles by Kim, J. S. Articles by Kim, D.-H. Related Articles Related Editorial

Promoter Methylation of Retinoic Acid Receptor Beta 2 and the Development of Second Primary Lung Cancers in Non–Small-Cell Lung Cancer

From the Center for Genome Research, Samsung Biomedical Research Institute; Division of Pulmonary and Critical Care Medicine, Department of Thoracic Surgery, and Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; Department of Molecular Cell Biology, Sungkyunkwan University, School of Medicine, Suwon, Korea

Address reprint requests to Duk-Hwan Kim, MD, ScD, Center for Genome Research, Samsung Biomedical Research Institute, Rm B155, #50 Ilwon-dong, Kangnam-Ku, Seoul, Korea, 135-710; e-mail: dukhwan{at}samsung.co.kr

PURPOSE: To investigate whether the promoter hypermethylation of retinoic acid receptor beta 2 (RARß2) is associated with the development of second primary lung cancers (SPLCs) differentially according to smoking status in primary non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: We retrospectively analyzed the relationship between RARß2 methylation and the SPLC development in a total of 342 NSCLCs. The methylation status of RARß2 was determined by using methylation-specific polymerase chain reaction. The difference in the time to SPLC development was analyzed by using the log-rank test and the Cox proportional hazards model. The median follow-up was 4.1 years.

RESULTS: SPLCs developed in 19 (5.6%) of the 342 NSCLCs, and overall incidence rate of SPLC development was 1.54 per 100 patient-years. SPLCs did not occur in 39 patients who had not smoked. After controlling for possible confounding factors, the hazard of failure for former smokers with RARß2 hypermethylation was about 2.87 (95% CI, 0.92 to 13.64; P = .08) times higher compared to those without RARß2 methylation. However, for current smokers, hypermethylation of the RARß2 was found to have a protective effect against the SPLC development (hazard ratio = 0.23; 95% CI, 0.11 to 0.87; P = .03).

CONCLUSION: Hypermethylation of RARß2 promoter had a differential effect on the development of SPLCs in NSCLC, and this was dependent on smoking status. Our study suggests that a combination of retinoids and/or a demethylating agent may be effective in the prevention of SPLCs in never-smokers and former smokers with NSCLC.

Supported by grants from the Samsung Biomedical Research Institute and the Samsung Advanced Institute of Technology.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

Related Editorial

• Retinoids in Lung Cancer: Friend, Foe, or Fellow Traveler?
  Fadlo R. Khuri and Reuben Lotan
  JCO 2004 22: 3435-3437 [Full Text]

This article has been cited by other articles:

				E.-S. Lee, J.-P. Issa, D. B. Roberts, M. D. Williams, R. S. Weber, M. S. Kies, and A. K. El-Naggar Quantitative Promoter Hypermethylation Analysis of Cancer-Related Genes in Salivary Gland Carcinomas: Comparison with Methylation-Specific PCR Technique and Clinical Significance Clin. Cancer Res., May 1, 2008; 14(9): 2664 - 2672. [Abstract] [Full Text] [PDF]

				M. D. Williams, N. Chakravarti, M. S. Kies, S.-I. Maruya, J. N. Myers, J. C. Haviland, R. S. Weber, R. Lotan, and A. K. El-Naggar Implications of Methylation Patterns of Cancer Genes in Salivary Gland Tumors Clin. Cancer Res., December 15, 2006; 12(24): 7353 - 7358. [Abstract] [Full Text] [PDF]

				Y. T. Kim, S. J. Park, S. H. Lee, H. J. Kang, S. Hahn, C. H. Kang, S. W. Sung, and J. H. Kim Prognostic implication of aberrant promoter hypermethylation of CpG islands in adenocarcinoma of the lung J. Thorac. Cardiovasc. Surg., November 1, 2005; 130(5): 1378 - 1378. [Abstract] [Full Text] [PDF]

				F. R. Hirsch and S. M. Lippman Advances in the Biology of Lung Cancer Chemoprevention J. Clin. Oncol., May 10, 2005; 23(14): 3186 - 3197. [Abstract] [Full Text] [PDF]

				Y. T. Kim, S. H. Lee, S. W. Sung, and J. H. Kim Can Aberrant Promoter Hypermethylation of CpG Islands Predict the Clinical Outcome of Non-Small Cell Lung Cancer After Curative Resection? Ann. Thorac. Surg., April 1, 2005; 79(4): 1180 - 1188. [Abstract] [Full Text] [PDF]