Azacitidine induces demethylation of the Epstein-Barr virus genome in tumors.
OBJECTIVE
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.


CONCLUSIONS
Pharmacologic reversal of dense CpG methylation in tumor tissue can be achieved in patients.
Department of Clinical Oncology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin NT, Hong Kong SAR, China.
Anthony T C
AT
Chan
Qian
Q
Tao
Keith D
KD
Robertson
Ian W
IW
Flinn
Risa B
RB
Mann
Barbara
B
Klencke
Wing Hong
WH
Kwan
Thomas Wai-Tong
TW
Leung
Philip J
PJ
Johnson
Richard F
RF
Ambinder
D000957:Antigens, Viral, Tumor / Q000378:metabolism; D001374:Azacitidine / Q000494:pharmacology*; D001483:Base Sequence; D019175:DNA Methylation; D004279:DNA, Viral / Q000378:metabolism; D015257:DNA-Cytosine Methylases; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004854:Herpesvirus 4, Human / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000821:virology; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000821:virology; D016133:Polymerase Chain Reaction / Q000379:methods; D011401:Promoter Regions, Genetic
D000957:Antigens, Viral, Tumor; D004279:DNA, Viral; D004791:Enzyme Inhibitors; C081573:DNA modification methylase SssI; D015257:DNA-Cytosine Methylases; D001374:Azacitidine