Aberrant DNA-Hypermethylation of Adenomatous Polyposis Coli (APC) and Death-Associated Protein Kinase (DAPK) in esophageal cancer: Association with response to neaodjuvant treatment and prognosis
Jan Brabender1, Daniel Vallbohmer1, Daniela Desombre1, Ralf Metzger1, Stephan E. Baldus2, Arnulf H. Holscher1, Paul M. Schneider1; 1Department of Visceral and Vascular Surgery, University of Cologne, Cologne, Germany; 2Dept. of Pathology, University of Cologne, Cologne, Germany
Introduction: Transcriptional silencing by DNA-Hypermethylation is one fundamental process involved in the development of many cancers and has been linked to worse prognose in esopahgeal cancer. However, the association of this epigenetic event with response to neoadjuvant radio-/chemotherapy in cancer of the esophagus has not been investigated. Aim of our study was to determine the association of APC and DAPK Hypermethylation with histomorphologic response to neoadjuvant radiochemotherapy in esophageal cancer. Material and Methods: 50 patients with resectable esophageal cancers (cT2-4, Nx, M0) received neoadjuvant radiochemotherapy (cisplatin, 5-FU, 36 Gy) followed by transthoracic en bloc esophagectomy. Histomorphologic regression was defined as major response when resected specimens contained less than 10 % of residual vital tumor cells. DNA was isolated from endoscopic biopsies (paired tumor and normal tissue) prior to neoadjuvant treatment. Quantitative methylation-specific real-time PCR (TaqMan™) assays were performed to determine methylation levels for DAPK and APC standardized for umethylated b-actin. Results: Median APC (p=0.003) and DAPK Methylation (p<0.001) levels were significantly higher in tumor tissues compared to paired normal tissues. APC and DAPK Methylation levels in tumor tissues showed no associations with response to neadjuvant radiochemotherapy, prognosis or patients clinical parameters. Histopathologic response to neadjuvant therapy was significantly associated with patients prognosis. The 5-year survival probabilities were 21.8%± 8.2 months for minor responders and 62.6% ± 12.9 months for major responders (p=0.009). Conclusion: These data show that hypermethylation of APC and DAPK is a common event in esophageal cancer and suggest a role for this epigenetic event in the development of this disease. However, hypermethylation of these genes is not associated with response to neadjuvant therapy and not useful as a clinical response marker. Response to neoadjuvant therapy is associated with patients prognosis in this disease.
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