Death-associated protein kinase (DAPK) promoter methylation and response to neoadjuvant radiochemotherapy in esophageal cancer.
BACKGROUND
Multiple studies have shown that promoter methylation of tumor suppressor genes underlies esophageal carcinogenesis. Hypothetically, methylation resulting in tumor suppressor gene inactivation might result in tumors that are unresponsive to chemotherapy and radiation. Accordingly, our aim was to investigate if aberrant methylation of the apoptosis-related gene Death-Associated Protein Kinase (DAPK) could be used as a predictor of response to neoadjuvant therapy in locally advanced cancer of the esophagus.


METHODS
Tumor and normal esophageal tissues were obtained from 50 patients with locally advanced cancer of the esophagus prior to neoadjuvant radiochemotherapy. DAPK methylation analysis was performed on all samples by methylation-specific real-time polymerase chain reaction (PCR).


RESULTS
Seventeen (34%) patients showed a major and 33 (66%) a minor histomorphological response to neoadjuvant therapy. DAPK methylation was detectable in normal esophageal tissues with a frequency of 10% and in tumor tissue with a frequency of 78%. The median methylation level for DAPK was 2.7 x 10(-3) in tumor compared with 0.1 x 10(-3) in normal tissues (p < 0.001). DAPK methylation was not associated with response to neoadjuvant therapy or prognosis after esophagectomy.


CONCLUSIONS
Aberrant DAPK methylation in tumor tissues is significantly higher compared with matching normal esophageal tissues, suggesting a fundamental role of this epigenetic alteration in the pathogenesis of this disease. The level of DAPK methylation in pretreatment biopsies of patients with locally advanced cancer of the esophagus is no marker for the prediction of histomorphological regression or prognosis following neoadjuvant chemoradiation in this disease.
Brabender
Jan
J
Department of General, Visceral and Tumor Surgery, University of Cologne, Cologne, Germany. jan.brabender@t-online.de
Arbab
Dariusch
D
Huan
Xi
X
Vallböhmer
Daniel
D
Grimminger
Peter
P
Ling
Frederike
F
Neiss
Susanne
S
Bollschweiler
Elfriede
E
Schneider
Paul M
PM
Hölscher
Arnulf H
AH
Metzger
Ralf
R
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000008:administration & dosage; D064550:Death-Associated Protein Kinases; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016629:Esophagectomy; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008297:Male; D008745:Methylation; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D011237:Predictive Value of Tests; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D018714:Radiotherapy, Adjuvant; D055815:Young Adult
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002945:Cisplatin; D005472:Fluorouracil