Prognostic importance of promoter hypermethylation of multiple genes in esophageal adenocarcinoma

Malcolm V. Brock, Mingzhou Gou, Yoshimitsu Akiyama, Alison Muller, Tsung Teh Wu, Elizabeth Montgomery, Mari Deasel, Paul Germonpré, Lewis Rubinson, Richard F. Heitmiller, Stephen C. Yang, Arlene A. Forastiere, Stephen B. Baylin, James G. Herman

Research output: Contribution to journalArticle

189 Scopus citations

Abstract

Purpose: We investigated aberrant methylation patterns in esophageal adenocarcinoma and correlated the findings to patient survival and tumor recurrence. Experimental Design: 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%; O6-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.

Original languageEnglish (US)
Pages (from-to)2912-2919
Number of pages8
JournalClinical Cancer Research
Volume9
Issue number8
StatePublished - Aug 1 2003

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Brock, M. V., Gou, M., Akiyama, Y., Muller, A., Wu, T. T., Montgomery, E., Deasel, M., Germonpré, P., Rubinson, L., Heitmiller, R. F., Yang, S. C., Forastiere, A. A., Baylin, S. B., & Herman, J. G. (2003). Prognostic importance of promoter hypermethylation of multiple genes in esophageal adenocarcinoma. Clinical Cancer Research, 9(8), 2912-2919.