Prognostic importance of promoter hypermethylation of multiple genes in esophageal adenocarcinoma.
OBJECTIVE
We investigated aberrant methylation patterns in esophageal adenocarcinoma and correlated the findings to patient survival and tumor recurrence.


METHODS
Gene promoter methylation was performed in 82 samples from 41 esophagectomy patients consisting of 41 adenocarcinoma samples, each with its adjacent nonmalignant tissue, which included one sample with Barretts metaplasia. The methylation status of seven genes was determined. Epigenetic silencing was confirmed using immunohistochemical staining. Kaplan-Meier plots were constructed using disease-specific survival as the primary end point and the interval from surgery to tumor recurrence as the secondary end point. The association of clinicopathological and biomolecular risk factors to survival and recurrence was performed using the Log-rank test and Cox proportional hazards model for multivariate analysis.


RESULTS
Methylation frequencies of the genes analyzed were APC, 68%; E-cadherin, 66%; O(6)-methylguanine DNA methyltransferase, 56%; ER, 51%; p16, 39%; DAP-kinase, 19%; and TIMP3, 19%. DNA methylation of some genes individually showed only trends toward diminished survival, whereas patients whose tumors had >50% of their gene profile methylated had both significantly poorer survival (P = 0.04) and earlier tumor recurrence (P = 0.05) than those without positive methylation. By multivariate analysis, the hazard ratios (HRs) with positive methylation status were more powerful predictors of survival [HR 2.7 (1.14-6.45; 95% confidence interval)] and tumor recurrence [HR 2.5 (1.11-5.6)] than age (HR 2.03 and 1.96, respectively) or stage (HR 1.48 and 1.67, respectively).


CONCLUSIONS
Our data suggest that positive methylation status for multiple genes in esophageal adenocarcinoma is a predictor of poor prognosis.
Brock
Malcolm V
MV
Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA. hermanji@jhmi.edu
Gou
Mingzhou
M
Akiyama
Yoshimitsu
Y
Muller
Alison
A
Wu
Tsung-Teh
TT
Montgomery
Elizabeth
E
Deasel
Mari
M
Germonpré
Paul
P
Rubinson
Lewis
L
Heitmiller
Richard F
RF
Yang
Stephen C
SC
Forastiere
Arlene A
AA
Baylin
Stephen B
SB
Herman
James G
JG
D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018899:CpG Islands; D004247:DNA / Q000737:chemistry; D019175:DNA Methylation; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000401:mortality; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome
D004247:DNA