Abstract
A hallmark of human cancer is global DNA hypomethylation (GDHO), but the mechanisms accounting for this defect and its pathological consequences have not been investigated in human epithelial ovarian cancer (EOC). In EOC, GDHO was associated with advanced disease and reduced overall and disease-free survival. GDHO (+) EOC tumors displayed a proliferative gene expression signature, including FOXM1 and CCNE1 overexpression. Furthermore, DNA hypomethylation in these tumors was enriched within genomic blocks (hypomethylated blocks) that overlapped late-replicating regions, lamina-associated domains, PRC2 binding sites, and the H3K27me3 histone mark. Increased proliferation coupled with hypomethylated blocks at late-replicating regions suggests a passive hypomethylation mechanism. This hypothesis was further supported by our observation that cytosine DNA methyltransferases (DNMTs) and UHRF1 showed significantly reduced expression in GDHO (+) EOC after normalization to canonical proliferation markers, including MKI67. Finally, GDHO (+) EOC tumors had elevated chromosomal instability (CIN), and copy number alterations (CNA) were enriched at the DNA hypomethylated blocks. Together, these findings implicate a passive DNA demethylation mechanism in ovarian cancer that is associated with genomic instability and poor prognosis.
Highlights
Altered DNA methylation, a fundamental characteristic of human cancer, includes gains and losses of methylation [1,2]
LINE-1 Hypomethylation is Associated with Disease Progression and Reduced Survival in epithelial ovarian cancer (EOC)
LINE-1 hypomethylation increased with advanced clinical stage and histopathological grade, and correlated with reduced overall increased with advanced clinical stage and histopathological grade, and correlated with reduced and disease-free survival (Figure 1a–d)
Summary
Altered DNA methylation, a fundamental characteristic of human cancer, includes gains and losses of methylation [1,2]. DNA hypermethylation leads to tumor suppressor gene silencing and occurs. Cancers 2020, 12, 764 frequently at genomic regions occupied by polycomb group proteins in embryonic stem cells [1,3]. DNA hypomethylation occurs at repetitive elements (RE), including the interspersed retrotransposon LINE-1 [7], which accounts for ~17% of the genome. Epigenomic approaches have revealed that GDHO is not random or driven solely by changes at RE, but rather is localized to large genomic regions referred to as hypomethylated blocks [14,15,16]. Hypomethylated blocks overlap lamina-associated domains (LADs) and, interestingly, can contain epigenetically silenced genes, as well as genomic regions showing high gene expression variability [15,17,18]
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