Abstract

<div>Abstract<p><b>Purpose:</b> Cancer germline (CG) antigens are frequently expressed and hypomethylated in epithelial ovarian cancer (EOC), but the relationship of this phenomenon to global DNA hypomethylation is unknown. In addition, the potential mechanisms leading to DNA hypomethylation, and its clinicopathologic significance in EOC, have not been determined.</p><p><b>Experimental Design:</b> We used quantitative mRNA expression and DNA methylation analyses to determine the relationship between expression and methylation of X-linked (<i>MAGE-A1</i>, <i>NY-ESO-1</i>, <i>XAGE-1</i>) and autosomal (<i>BORIS</i>, <i>SOHLH2</i>) CG genes, global DNA methylation (5mdC levels, <i>LINE-1</i>, <i>Alu</i>, and <i>Sat-α</i> methylation), and clinicopathology, using 75 EOC samples. In addition, we examined the association between these parameters and a number of mechanisms proposed to contribute to DNA hypomethylation in cancer.</p><p><b>Results:</b> CG genes were coordinately expressed in EOC and this was associated with promoter DNA hypomethylation. Hypomethylation of CG promoters was highly correlated and strongly associated with <i>LINE-1</i> and <i>Alu</i> methylation, moderately with 5mdC levels, and rarely with <i>Sat-α</i> methylation. <i>BORIS</i> and <i>LINE-1</i> hypomethylation, and <i>BORIS</i> expression, were associated with advanced stage. <i>GADD45A</i> expression, <i>MTHFR</i> genotype, <i>DNMT3B</i> isoform expression, and <i>BORIS</i> mRNA expression did not associate with methylation parameters. In contrast, the <i>BORIS/CTCF</i> expression ratio was associated with DNA hypomethylation, and furthermore correlated with advanced stage and decreased survival.</p><p><b>Conclusions:</b> DNA hypomethylation coordinately affects CG antigen gene promoters and specific repetitive DNA elements in EOC, and correlates with advanced stage disease. The <i>BORIS</i>/<i>CTCF</i> mRNA expression ratio is closely associated with DNA hypomethylation and confers poor prognosis in EOC. <i>Clin Cancer Res; 17(8); 2170–80. ©2011 AACR</i>.</p></div>

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