Studies of methylation changes during human ovarian cancer development
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Previous epigenetic studies have shown that gene expression is inversely correlated with promoter methylation status. DNA methylation changes are a hallmark of cancer development. Two seemingly opposite events have been reported in almost all types of cancers, a global decrease of methylation (hypomethylation) and a gene specific increase of methylation (hypermethylation). The current thesis provides a study of methylation changes in ovarian cancer development. The hypothesis that hypomethylation of retroelements may contribute significantly to global hypomethylation in cancer was tested by examining two families of retrotransposons. Retrotransposons are repetitive sequences widespread through the genome and generally methylated in non-malignant cells. A decrease of methylation levels of HERV-W and LINE1 was detected in ovarian adenocarcinoma compared with benign adenomas. Gene hypermethylation and hypomethylation were also studied at the specific gene level. To study gene hypermethylation changes, the ovarian cancer cell line OVCAR3 was globally demethylated by 5-aza-deoxycytidine treatment. Comparison of those genes with genes downregulated in ovarian adenocarcinoma provides a list of candidate genes hypermethylated during ovarian cancer development. The presence of a CpG island in the promoter region of HLA-G and its upregulation in multiple cancer tissues make this gene a likely candidate for hypomethylation changes. Previous studies conducted in cancer cell lines have demonstrated a correlation between hypomethylation of a CpG rich sequence in the HLA-G promoter and increased expression. We studied the expression and methylation levels of HLA-G in ovarian tissue, and found no apparent correlation. Opposite results were obtained from an ovarian cancer cell line (BG-1), for which loss of methylation correlated with an increase of expression. Results suggest a different control mechanism for HLA-G expression between the ovarian cancer cell lines and ovarian tissue.