Originally published as JCO Early Release 10.1200/JCO.2004.04.185 on March 8 2004

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Azacitidine Induces Demethylation of the Epstein-Barr Virus Genome in Tumors

From the Department of Clinical Oncology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin NT, Hong Kong SAR, China; Cancer Epigenetics/Tumor Virology Laboratory, Johns Hopkins Singapore, Singapore; Epigenetic Gene Regulation and Cancer Section, National Cancer Institute, National Institutes of Health, Bethesda; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Department of Medicine, University of California San Francisco-Mt. Zion Hospital, San Francisco, CA

Address reprint requests to Richard F. Ambinder, MD, PhD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Bldg Rm 389, 1650 Orleans St, Baltimore, MD 21231; e-mail: ambinri{at}jhmi.edu

PURPOSE: To determine whether therapy with a DNA methyltransferase inhibitor is effective in achieving demethylation and gene re-expression in tumor DNA in patients.

METHODS: Biopsy specimens were obtained from patients with Epstein-Barr virus-associated tumors, enrolled on a clinical trial of 5-azacitidine, within 72 hours of the conclusion of the last infusion of the first cycle of therapy, and compared to pretreatment specimens. Methylation-specific polymerase chain reaction, bisulfite genomic sequencing, and immunohistochemistry were used to assess demethylation and gene re-expression.

RESULTS: Substantial degrees of demethylation were detected in all latent and lytic Epstein-Barr virus promoters examined. Immunohistochemistry suggested activation of a previously silent viral antigen expression in one instance.

CONCLUSION: Pharmacologic reversal of dense CpG methylation in tumor tissue can be achieved in patients.

Research funded by National Institutes of Health grants PO1 CA15396 "EBV-related tumors" and UOI CA70062 "AIDS-associated malignancies clinical trials in a cooperative group."

Anthony T.C. Chan and Qian Tao contributed equally to the work.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

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