Abstract
DNA methylation is well-known to be associated with ovarian cancer (OC) and has great potential to serve as a biomarker in monitoring response to therapy and for disease screening. The purpose of this study was to investigate methylation of HNF1B and GATA4 and correlate detected methylation with clinicopathological characteristic of OC patients. The study group consisted of 64 patients with OC and 35 control patients. To determine the most important sites of HNF1B and GATA4, we used next-generation sequencing. For further confirmation of detected methylation of selected regions, we used high-resolution melting analysis and methylation-specific real-time polymerase chain reaction (PCR). Selected regions of HNF1B and GATA4 were completely methylation free in all control samples, whereas methylation-positive pattern was observed in 32.8% (HNF1B) and 45.3% (GATA4) of OC samples. Evaluating both genes together, we were able to detect methylation in 65.6% of OC patients. We observed a statistically significant difference in HNF1B methylation between samples with different stages of OC. We also detected subtype specific methylation in GATA4 and a decrease of methylation in late stages of OC. The combination of unmethylated HNF1B and methylated GATA4 was associated with longer overall survival. In our study, we employed innovative approach of methylation analysis of HNF1B and GATA4 to search for possible epigenetic biomarkers. We confirmed the significance of the HNF1B and GATA4 hypermethylation with emphasis on the need of selecting the most relevant sites for analysis. We suggest selected CpGs to be further examined as a potential positive prognostic factor.
Highlights
Ovarian cancer (OC) includes several types of cancer that arise from different cells within the ovary
The DNA methylation profile in nine cancerous and six control samples is depicted in Figure 1 (HNF1B gene) and Figure 2 (GATA4 gene)
Considering the statistically significantly higher HNF1B methylation in the late stages of OC, we focused on further analysis of both genes combinations
Summary
Ovarian cancer (OC) includes several types of cancer that arise from different cells within the ovary. Due to the lack of any specific symptoms in early stages, most cases of OC are diagnosed at an advanced stage after the disease has spread beyond the ovary. The aggressive nature of the disease, in addition to the lack of effective screening test, causes OC to have the worst mortality rate of all female reproductive system cancers. The most commonly-occurring epigenetic event taking place in the mammalian genome is DNA methylation, the addition of a methyl group to the 5 -carbon of cytosine in CpG sequences. It has been suggested that epigenetic alterations have a great potential to serve as biomarkers in monitoring response to therapy and for disease screening and detection [6]. Many different genes have been identified as being hypermethylated and silenced in ovarian carcinoma [7,8]
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