Aberrant Methylation Status of Tumour Suppressor Genes in Ovarian Cancer Tissue and Paired Plasma Samples

Abstract

Ovarian cancer is a highly heterogeneous disease and its formation is affected by many epidemiological factors. It has typical lack of early signs and symptoms, and almost 70% of ovarian cancers are diagnosed in advanced stages. Robust, early and non-invasive ovarian cancer diagnosis will certainly be beneficial. Herein we analysed the regulatory sequence methylation profiles of the RASSF1, PTEN, CDH1 and PAX1 tumour suppressor genes by pyrosequencing in healthy, benign and malignant ovarian tissues, and corresponding plasma samples. We recorded statistically significant higher methylation levels (p < 0.05) in the CDH1 and PAX1 genes in malignant tissues than in controls (39.06 ± 18.78 versus 24.22 ± 6.93; 13.55 ± 10.65 versus 5.73 ± 2.19). Higher values in the CDH1 gene were also found in plasma samples (22.25 ± 14.13 versus 46.42 ± 20.91). A similar methylation pattern with positive correlation between plasma and benign lesions was noted in the CDH1 gene (r = 0.886, p = 0.019) and malignant lesions in the PAX1 gene (r = 0.771, p < 0.001). The random forest algorithm combining methylation indices of all four genes and age determined 0.932 AUC (area under the receiver operating characteristic (ROC) curve) prediction power in the model classifying malignant lesions and controls. Our study results indicate the effects of methylation changes in ovarian cancer development and suggest that the CDH1 gene is a potential candidate for non-invasive diagnosis of ovarian cancer.

Epithelial ovarian cancer and the use of circulating tumor DNA: A systematic review

“…The remaining four studies focused on methylations in tumor and ctDNA in more than one gene. Ibanez de Caceres et al mainly focused on two genes and detected concordant methylation status in tumor and ctDNA in 93% of the patients [18], and Dvorska et al identified a significant correlation coefficient in methylation status of CHD1 and PAX1 between tumor and ctDNA [19]. Two studies determined the methylation profile in six and seven genes, respectively.…”

Can Circulating Cell-Free DNA or Circulating Tumor DNA Be a Promising Marker in Ovarian Cancer?

“…There were several methylation changes in tissues and corresponding plasma samples of ovarian cancer. For example, Dvorská D et al [ 42 ] showed that, in the tissues of malignant ovarian cancer patients, the methylation levels of CDH1 gene were higher than those of healthy controls, and the difference was statistically significant. Methylation of CDH1 gene was also highly expressed in the corresponding plasma samples.…”

Role of miRNA manipulation on methylation states of breast cancer stem cell-related gene: Methylation status and miRNAs on BCSCs

“…Tumor suppressor genes can be deactivated by either hypermethylation of the promoter region or mutation. The abnormal increase of methylation in the promoter region of tumor suppressor genes has been reported in BC such as CDH1, RASSF1A, and BRCA1 37 .…”