J Lung Cancer.
2004 Dec;3(2):77-85.
Correlation between Aberrant Promoter Hypermethylation of CpG Islands and the Clinical Outcome of Non-small Cell Lung Cancer after Curative Resection
- Affiliations
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- 1Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, Cancer Research Institute, Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea. ytkim@snu.ac.kr
Abstract
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PURPOSE: Aberrant methylation of CpG islands has been suggested as one of the cause for development of cancer by forcing specific tumor suppressor gene function. The methylation status of primary non-small cell lung cancer (NSCLC) was investigated and its clinical relevance was tested whether it could predict the clinical outcomes after curative resection.
MATERIALS AND METHODS
We analyzed 61 tissue samples from NSCLC patients using methylation-specific PCR (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 p16INK4a, 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 RARbetagene 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
