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J Thorac Cardiovasc Surg 2005;130:1378
© 2005 The American Association for Thoracic Surgery

General Thoracic Surgery

Prognostic implication of aberrant promoter hypermethylation of CpG islands in adenocarcinoma of the lung

Young Tae Kim, MD, PhD a , * , Sun Jung Park, MS a , Seung Hee Lee, BS a , Hee Jung Kang, MD, PhD b , Seokyung Hahn, PhD c , Chang Hyun Kang, MD a , Sook Whan Sung, MD, PhD a , Joo Hyun Kim, MD, PhD a

a Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, and the Cancer Research Institute, Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea
b Department of Laboratory Medicine, Hallym University College of Medicine, Anyang, Korea
c Medical Research Collaborating Center, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Read at the Eighty-fifth Annual Meeting of The American Association for Thoracic Surgery, San Francisco, Calif, April 10-13, 2005.

Received for publication April 7, 2005; revisions received April 28, 2005; accepted for publication June 7, 2005.

* Address for reprints: Young Tae Kim, MD, PhD, Thoracic and Cardiovascular Surgery, Seoul National University Hospital, 28 Yongun-Dong, Chongno-Ku, Seoul, 110-744, Republic of Korea (Email: ytkim{at}snu.ac.kr).

OBJECTIVES: DNA hypermethylation in promoter regions has been studied for various types of cancer. However, there is no clear evidence that shows whether methylation status can predict long-term survival in patients with lung cancer.

METHODS: We collected tissues from 72 patients with lung adenocarcinomas. The cancer and normal lung tissues were tested for DNA hypermethylation by using methylation-specific polymerase chain reaction. The genes investigated were p16INK4{alpha}(p16), retinoic acid receptor ß-promoter (RARßP2), death-associated protein kinase (DAPK), O6-methylguanine-DNA-methyltransferase (MGMT), and glutathione-S-transferase P1 (GSTP1). The status of the DNA methylation was analyzed, and we focused on long-term outcomes, as well as other clinical variables.

RESULTS: DNA hypermethylation was observed in 83% for p16, 63% for RARßP2, 32% for DAPK, 17% for MGMT, and 46% for GSTP1 from the cancer tissue. From normal lung tissue, the results of methylation were positive in 75% for p16, 24% for RARßP2, 10% for DAPK, 6% for MGMT, and 33% for GSTP1. During the mean follow-up period of 18 ± 11 months (1-40 months), 25 (35%) patients experienced recurrence, and 13 died. In multivariable analysis, old age (>60 years, P = .007), male sex (P = .004), unmethylation of DAPK from cancer tissue (P = .045), and hypermethylation of RARßP2 from normal tissue (P = .000) were risk factors for poor survival. Pathologic stage (P = .023), unmethylation of DAPK from normal tissue (P = .043), and hypermethylation of RARßP2 from normal tissue (P = .030) were risk factors for disease-free survival.

CONCLUSIONS: DNA methylation status of CpG islands seems to be a useful predictor of long-term outcome for adenocarcinoma of the lung. However, because the predictive power is still low, further studies, including those with multiple genes, are necessary to increase its usefulness in the clinical setting.




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