Can aberrant promoter hypermethylation of CpG islands predict the clinical outcome of non-small cell lung cancer after curative resection?

Ann Thorac Surg. 2005 Apr;79(4):1180-8; discussion 1180-8. doi: 10.1016/j.athoracsur.2004.09.060.


Background: Aberrant methylation of CpG islands acquired in tumor cells in promoter regions is one cause for the loss of gene function. We examined whether aberrant DNA hypermethylation could be used to predict the clinical outcomes of patients with primary nonsmall cell lung cancer (NSCLC) after curative resection.

Methods: We tested 61 patients with NSCLC using methylation-specific polymerase chain reaction (MSP) and searched for promoter hypermethylation of the genes p16INK4a, retinoic acid receptor beta-promoter (RARbetaP2), death-associated protein kinase (DAPK), and O6-methylguanine-DNA-methyltransferase (MGMT). The clinical data, the presence of DNA hypermethylation, and clinical outcomes were analyzed.

Results: Hypermethylation in the tumor samples was detected in 67% (41 of 61) for p16(INK4a), 49% (30 of 61) for RARbetaP2, 30% (18 of 61) for DAPK, and 62% (38 of 61) for MGMT. Thirty patients (49%) developed recurrence within 33 months; 16 in the remaining lung, 10 in other organs, and 4 in both. We found no correlation between the specific DNA hypermethylation and any of the clinicopathological characteristics of the patients. DNA hypermethylation was not associated with a different survival or recurrence rate. However, the aberrant hypermethylation of RARbetaP2 seemed to be related to the location of cancer recurrence. Although advanced T stage and preoperative chemotherapy were statistically significant in univariate analysis, unmethylation of DAPK (p = 0.030) and hypermethylation of RARbetaP2 (p = 0.014), as well as advanced T stage (p = 0.075) and preoperative chemotherapy (p = 0.025), were significant risk factors in multivariate analysis for early recurrence in the remaining lung.

Conclusions: The P2 hypermethylation of the RARbeta gene and unmethylation of DAPK seem to be important factors in predicting early cancer recurrence in the remaining lung and could be used as a prognostic marker in NSCLC. However, the clinical implications of this finding need further investigation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Apoptosis Regulatory Proteins
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carcinoma, Non-Small-Cell Lung / surgery*
  • Combined Modality Therapy
  • CpG Islands*
  • DNA Methylation*
  • Death-Associated Protein Kinases
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / surgery*
  • Middle Aged
  • Neoplasm Recurrence, Local
  • Neoplasm Staging
  • O(6)-Methylguanine-DNA Methyltransferase / genetics
  • Promoter Regions, Genetic*
  • Receptors, Retinoic Acid / genetics


  • Apoptosis Regulatory Proteins
  • Receptors, Retinoic Acid
  • retinoic acid receptor beta
  • O(6)-Methylguanine-DNA Methyltransferase
  • Death-Associated Protein Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases