Comprehensive methylome analysis of ovarian tumors reveals hedgehog signaling pathway regulators as prognostic DNA methylation biomarkers

Abstract

Women with advanced stage ovarian cancer (OC) have a five-year survival rate of less than 25%. OC progression is associated with accumulation of epigenetic alterations and aberrant DNA methylation in gene promoters acts as an inactivating ?hit? during OC initiation and progression. Abnormal DNA methylation in OC has been used to predict disease outcome and therapy response. To globally examine DNA methylation in OC, we used next-generation sequencing technology, MethylCap-sequencing, to screen 75 malignant and 26 normal or benign ovarian tissues. Differential DNA methylation regions (DMRs) were identified, and the Kaplan?Meier method and Cox proportional hazard model were used to correlate methylation with clinical endpoints. Functional role of specific genes identified by MethylCap-sequencing was examined in in vitro assays. We identified 577 DMRs that distinguished (p < 0.001) malignant from non-malignant ovarian tissues; of these, 63 DMRs correlated (p < 0.001) with poor progression free survival (PFS). Concordant hypermethylation and corresponding gene silencing of sonic hedgehog pathway members ZIC1 and ZIC4 in OC tumors was confirmed in a panel of OC cell lines, and ZIC1 and ZIC4 repression correlated with increased proliferation, migration and invasion. ZIC1 promoter hypermethylation correlated (p < 0.01) with poor PFS. In summary, we identified functional DNA methylation biomarkers significantly associated with clinical outcome in OC and suggest our comprehensive methylome analysis has significant translational potential for guiding the design of future clinical investigations targeting the OC epigenome. Methylation of ZIC1, a putative tumor suppressor, may be a novel determinant of OC outcome.

Ras-induced Epigenetic Inactivation of the RRAD (Ras-related Associated with Diabetes) Gene Promotes Glucose Uptake in a Human Ovarian Cancer Model

“…Most of them were related to cancer and metabolism. Some of these pathways were reported in ovarian cancers by Huang et al (54). Further, the comparison of the methylation level between T29 and T29H revealed that T29H had slight decrease in the methylation level of C and CpG (Fig.…”

Distinct methylation profile of mucinous ovarian carcinoma reveals susceptibility to proteasome inhibitors

“…The first dataset was our methyl‐CpG binding domain of the MBD2 protein to capture double‐stranded DNA followed by high‐throughput next‐generation sequencing (MethylCap‐seq) dataset, which included MuOC ( n  = 16), SeOC ( n  = 50) and benign mucinous adenoma ( n  = 6) (Supporting Information, Table S1). We performed the methylation level by sequencing of fragmentally methylated DNA 29. Another dataset was deposited in NCBI's Gene Expression Omnibus (GEO) with accession number GSE51820 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE51820).…”

Mutual regulation of microRNAs and DNA methylation in human cancers

“…54 Significant increase of DNMT1 expression has been associated with tumorigenesis in colon cancer. Among other epigenetic changes, aberrant de novo hypermethylation of many tumor suppressor genes has been shown to play a crucial role in many malignancies including, lung and ovarian cancer 55,56 .…”