Coordinated Cancer Germline Antigen Promoter and Global DNA Hypomethylation in Ovarian Cancer: Association with the BORIS/CTCF Expression Ratio and Advanced Stage

Abstract

Purpose: 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.Experimental Design: We used quantitative mRNA expression and DNA methylation analyses to determine the relationship between expression and methylation of X-linked (MAGE-A1, NY-ESO-1, XAGE-1) and autosomal (BORIS, SOHLH2) CG genes, global DNA methylation (5mdC levels, LINE-1, Alu, and Sat-a 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.Results: 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 LINE-1 and Alu methylation, moderately with 5mdC levels, and rarely with Sat-a methylation. BORIS and LINE-1 hypomethylation, and BORIS expression, were associated with advanced stage. GADD45A expression, MTHFR genotype, DNMT3B isoform expression, and BORIS mRNA expression did not associate with methylation parameters. In contrast, the BORIS/CTCF expression ratio was associated with DNA hypomethylation, and furthermore correlated with advanced stage and decreased survival.Conclusions: DNA hypomethylation coordinately affects CG antigen gene promoters and specific repetitive DNA elements in EOC, and correlates with advanced stage disease. The BORIS/CTCF mRNA expression ratio is closely associated with DNA hypomethylation and confers poor prognosis in EOC. Clin Cancer Res; 17(8); 2170-80. Ó2011 AACR.

BORIS, Brother of the Regulator of Imprinted Sites, Is Aberrantly Expressed in Hepatocellular Carcinoma

“…In epithelial ovarian cancer, the BORIS/CTCF expression ratio is also associated with a higher stage of tumor and decreased rate of survival (Woloszynska-Read et al, 2011). It has been suggested that the expression of BORIS displaces CTCF in the genome and leads to proliferation of cancer cells.…”

Transcription Factor BORIS (Brother of the Regulator of Imprinted Sites) Directly Induces Expression of a Cancer-Testis Antigen, TSP50, through Regulated Binding of BORIS to the Promoter

“…Furthermore, it has been reported that BORIS regulates expression of genes encoding other CTAs including MAGE-A1, SPANX, and NY-ESO-1 (30,31). Recent publications suggested BORIS was involved in DNA hypomethylation in cancers that is important for derepression of CTAs expression (32,33). These studies suggest that BORIS is an important regulator of CTA expression in cancer cells.…”

DNA methylation and nucleosome occupancy regulate the cancer germline antigen geneMAGEA11

“…We also analyzed MAGEA11 expression in human EOC, which has proven a useful disease model to study CG antigen gene regulation. [18][19][20] Oncomine analysis of the Cancer Genome Atlas (TCGA) high-grade serous ovarian cancer data revealed significant elevation of MAGEA11 expression in EOC as compared with normal ovary (Fig. 2A).…”