Genomic and epigenomic characterization of global DNA hypomethylation in human epithelial ovarian cancer
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Epithelial ovarian cancer (EOC), and all other solid tumor types investigated to date, contain a variable proportion of tumors characterized by global DNA hypomethylation (GDHO). This phenotype is known to involve loss of DNA methylation at repetitive elements and at single copy gene promoters of cancer germline (CG)/cancer testis (CT) antigens. GDHO in EOC has also been linked to tumor progression and reduced survival. Despite the apparent clinical importance of DNA hypomethylation, we currently have a limited understanding of the origin, the targets, and the consequences of GDHO in EOC. To reveal the underlying mechanisms and molecular pathology of GDHO in cancer, we used gene expression profiling and methylome sequencing to determine the molecular differences between hypomethylated EOC samples and normally methylated EOC samples. The gene expression pattern was distinct in hypomethylated EOC, with more than half of differentially expressed genes (DEGs) upregulated. A large number of epigenetic related genes and histones were differentially expressed in hypomethylated EOC. In addition, many CG antigens were upregulated in hypomethylated EOC, including those not previously known to be regulated by DNA methylation in EOC, for example PRAME and CT45. Notably, one of the most significantly altered pathways in hypomethylated tumors was cellular growth and proliferation, including the FOXM1 pathway, implicating enhanced proliferation in phenotype. Methylome analysis revealed that DNA hypomethylation is not evenly dispersed across the genome, but is regionally localized, including prominent alterations at nuclear lamina associated domains (LADs). Taken together, our data show that DNA hypomethylation in EOC is linked to global gene activation, proliferation, and nuclear disorganization. These mechanisms may account for the poor prognosis and reduced survival of patients showing DNA hypomethylation. Our study is the first detailed investigation of the genomic and the epigenomic characteristics of GDHO in human epithelial EOC, and sheds light on the connection of this important epigenetic phenotype with carcinogenesis.