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Intertumor and intratumor NY-ESO-1 expression heterogeneity is associated with promoter-specific and global DNA methylation status in ovarian cancer.


ABSTRACT: 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.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.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.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.

SUBMITTER: Woloszynska-Read A 

PROVIDER: S-EPMC2835568 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Intertumor and intratumor NY-ESO-1 expression heterogeneity is associated with promoter-specific and global DNA methylation status in ovarian cancer.

Woloszynska-Read Anna A   Mhawech-Fauceglia Paulette P   Yu Jihnhee J   Odunsi Kunle K   Karpf Adam R AR  

Clinical cancer research : an official journal of the American Association for Cancer Research 20080601 11


<h4>Purpose</h4>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.<h4>Experimental design</h4>We utilized 78 EOC tumors and 10 normal ovary controls for quantitative DNA methylatio  ...[more]

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