This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Woloszynska-Read, A. Articles by Karpf, A. R. Search for Related Content PubMed PubMed Citation Articles by Woloszynska-Read, A. Articles by Karpf, A. R.

Intertumor and Intratumor NY-ESO-1 Expression Heterogeneity Is Associated with Promoter-Specific and Global DNA Methylation Status in Ovarian Cancer

Authors' Affiliations: Departments of ¹ Pharmacology and Therapeutics, ² Pathology, ³ Biostatistics, and ⁴ Immunology, Roswell Park Cancer Institute, Buffalo, New York

Requests for reprints: Adam R. Karpf, Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-8305; Fax: 716-845-8857; E-mail: adam.karpf{at}roswellpark.org.

Purpose: The cancer/germline antigen NY-ESO-1 is variably expressed in epithelial ovarian cancer (EOC), with most tumors showing low or heterogeneous expression, which limits patient responses to NY-ESO-1 vaccine therapy. We tested the hypothesis that promoter and global genomic DNA methylation status correlates with intertumor and intratumor NY-ESO-1 expression status in EOC.

Experimental Design: We utilized 78 EOC tumors and 10 normal ovary controls for quantitative DNA methylation analyses and NY-ESO-1 expression analysis by immunohistochemistry (IHC) and quantitative reverse transcriptase PCR. A subset of EOC tumors were used to perform microdissections of NY-ESO-1 IHC-positive and NY-ESO-1 IHC-negative tissue regions, followed by DNA methylation analyses. EOC cell lines were treated in vitro with decitabine to determine the functional contribution of DNA methylation to NY-ESO-1 gene regulation in EOC.

Results: Compared with normal ovary, bulk EOC tissues display increased NY-ESO-1 expression, reduced NY-ESO-1 promoter methylation, and reduced LINE-1 DNA methylation. However, NY-ESO-1 expression is not significantly associated with NY-ESO-1 promoter methylation status in bulk tumors. We hypothesized that this resulted from heterogeneous intratumor NY-ESO-1 expression. Supporting this idea, experiments using microdissected material revealed that intertumor and intratumor NY-ESO-1 expression heterogeneity is significantly correlated with promoter and global DNA methylation status in EOC. Moreover, decitabine treatment functionally restored NY-ESO-1 expression in nonexpressing EOC cell lines.

Conclusion: DNA methylation status is associated with both intertumor and intratumor NY-ESO-1 expression status in EOC. These findings support a novel chemoimmunotherapy approach using decitabine to augment NY-ESO-1 vaccine therapy for treatment of recurrent EOC.

This article has been cited by other articles:

				P. A. Link, M. R. Baer, S. R. James, D. A. Jones, and A. R. Karpf p53-Inducible Ribonucleotide Reductase (p53R2/RRM2B) Is a DNA Hypomethylation-Independent Decitabine Gene Target That Correlates with Clinical Response in Myelodysplastic Syndrome/Acute Myelogenous Leukemia Cancer Res., November 15, 2008; 68(22): 9358 - 9366. [Abstract] [Full Text] [PDF]