Methylated DAPK and APC promoter DNA detection in peripheral blood is significantly associated with apparent residual tumor and outcome.
BACKGROUND
Death-associated protein kinase (DAPK) and adenomatous polyposis coli gene (APC) have been recently shown to be associated with outcome in patients with esophageal carcinoma, especially adenocarcinoma. We wanted to validate the correlation of these two markers with outcome by detecting methylated DNA sequences in peripheral blood.


METHODS
Circulating cell-free DNA extracted from blood plasma of 59 patients with esophageal cancer was analyzed before and after surgical resection by quantitative real-time methylation-specific RT-PCR (TaqMan) assays.


RESULTS
Thirty-six of 59 patients (61.0%) with esophageal cancer had detectable levels of methylated DAPK or APC promoter DNA and preoperative detection was significantly associated with an unfavorable prognosis as revealed by multivariate Cox proportional hazards regression analysis [Exp(b) = 4.578; P = 0.01]. The combination of both markers significantly increased sensitivity and specificity for discriminating between short (<2.5 years) and long survivors (P = 0.04, ROC curve analysis). Postoperative APC detection was significantly different if residual tumor was apparent (P = 0.03).


CONCLUSIONS
Preoperative measurement of methylated DAPK and APC promoter DNA in peripheral blood may contribute to better estimate postoperative survival chances of patients with esophageal carcinoma, especially adenocarcinoma. The postoperative detection of methylated APC in peripheral blood might provide crucial information on apparent residual tumor and might be used as a "molecular" R0-Marker in addition to the pathologic examination.
Hoffmann
Andreas-Claudius
AC
Department of Medicine (Cancer Research), West German Cancer Center, University Hospital Essen, 45122 Essen, Germany. ach@o117.com
Vallböhmer
Daniel
D
Prenzel
Klaus
K
Metzger
Ralf
R
Heitmann
Michaela
M
Neiss
Susanne
S
Ling
Fredericke
F
Hölscher
Arnulf H
AH
Schneider
Paul M
PM
Brabender
Jan
J
D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics*; D004273:DNA, Neoplasm / Q000097:blood* / Q000235:genetics; D064550:Death-Associated Protein Kinases; D004938:Esophageal Neoplasms / Q000097:blood / Q000235:genetics* / Q000601:surgery; D006801:Humans; D015999:Multivariate Analysis; D018365:Neoplasm, Residual / Q000097:blood / Q000235:genetics* / Q000601:surgery; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012372:ROC Curve; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D015996:Survival Rate; D016896:Treatment Outcome
D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases