Cancer/Germline (CG) antigens and epigenetic deregulation in human epithelial ovarian cancer (EOC)
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Cancer/Germline (CG) antigen genes have been utilized as immunotherapeutic targets in vaccine-based anti-cancer treatments. Although this approach elicits immune responses and promising outcomes in patients, obstacles such as low and heterogeneous antigen levels are problematic. Recent studies have demonstrated that epigenetic silencing is a key mechanism leading to inactivation of CG antigens in normal somatic tissues. Conversely, in germ cells, trophoblasts, and various cancers, CG genes are often expressed, and their promoters are hypomethylated, which allows for transcription. Although DNA methylation clearly plays a regulatory role in the expression of CG antigens, the exact mechanism of establishing methylation signals in the promoter regions of these genes is still unknown. Due to their highly restricted expression in normal tissues and spontaneous induction of immune responses in cancer patients, CG antigens have generated great clinical interest. Moreover, a number of studies indicate that CG antigens are induced after treatment with the demethylating agent, 5-aza-2'-deoxycytidine, in cell culture and cancer patients. This observation directly suggests that the expression pattern of those genes depends on DNA methylation signals that are removed after treatment. The objectives of this dissertation are (1) to characterize expression and promoter methylation of CG antigen genes in ovarian cancer patient clinical samples; (2) to explore relationships between CG antigens expression and other epigenetic parameters; and more generally, (3) to understand aberrant epigenetic mechanisms and their contribution to ovarian tumorigenesis. We hypothesized that promoter hypomethylation is a major mechanism that leads to CG antigen expression in EOC. Furthermore, we hypothesized that expression of CG antigens is inversely associated with global hypomethylation of the genome. This study characterizes in detail a number of epigenetic parameters in a large set of human ovarian tumors. We demonstrate that expression of CG antigens in ovarian tumors is often upregulated, and their promoters hypomethylated, when compared to normal corresponding tissue. We further find that global DNA methylation patterns are altered in EOC specimens. Specifically, we discovered that LINE-1 repetitive elements are hypomethylated in EOC, and this significantly correlates with levels of 5mdC in the genome. Notably, CG promoter methylation showed a strong correlation with LINE-1 methylation, suggesting a sequence-specific hypomethylation defect in ovarian cancer that affects both X-linked and autosomal CG antigen gene promoters, as well as LINE-1 elements. CG antigen genes are often heterogeneously expressed in cancer. This is a limiting factor to the employment of vaccine approaches in the clinic. To investigate the origin of expression heterogeneity of NY-ESO-1, we analyzed in vivo samples of human ovarian tumors. To determine whether NY-ESO-1 (CG-X antigen) protein expression correlated with the amount of DNA methylation within the NY-ESO-1 gene promoter sequence, we microdissected ovarian tumors and selected for NY-ESO-1 positive and negative cell populations. Notably, our findings provide evidence that DNA methylation regulates NY-ESO-1 expression in ovarian cancer, which points towards the use of DNA methylation inhibitors in combination with a NY-ESO-1 vaccine as a treatment for ovarian cancer. The intra-tumor heterogeneity was strongly correlative with NY-ESO-1 promoter hypomethylation and global DNA hypomethylation. NY-ESO-1 expression heterogeneity is not only observed at the intra-tumor level but also among different tumors. Our findings showed, for the first time, that intra-tumor heterogeneity of protein expression in clinical samples is associated with the epigenetic status of the gene promoter and genomic DNA. The mechanism of CG activation in cancer has not been elucidated, but the newly discovered BORIS protein has been implicated in transcriptional regulation of CG antigens via promoter demethylation. In our study, we first showed that BORIS itself is controlled by promoter DNA methylation. Second, we examined whether BORIS expression is functionally involved in epigenetic deregulation in ovarian cancer cells. We utilized an adenoviral approach to exogenously express BORIS, and RNAi to knockdown BORIS. We followed this by a direct analysis of various epigenetic parameters. Our results suggest that BORIS does not play a direct role in driving CG antigen gene expression, promoter hypomethylation, or global DNA hypomethylation in ovarian cancer cells. In summary, this dissertation reveals that ovarian cancer is characterized by a global DNA hypomethylation defect that coordinately affects BORIS, CG antigen genes, and repetitive DNA elements, but that BORIS expression may not directly drive this process. We expect that these findings will significantly impact the field of cancer epigenetics. More importantly, they will facilitate development of new and improved immunotherapeutic approaches in the treatment of ovarian cancer.
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