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. 2019 Aug 23;20(17):4119.
doi: 10.3390/ijms20174119.

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

Dana Dvorská  1 , Dušan Braný  2 , Bálint Nagy  3 , Marián Grendár  4 , Robert Poka  5 , Beáta Soltész  3 , Marianna Jagelková  6   7 , Katarína Zelinová  6   7 , Zora Lasabová  7 , Pavol Zubor  6 , Zuzana Danková  7
Affiliations

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

Dana Dvorská et al. Int J Mol Sci. .

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.

Keywords: CDH1; PAX1; PTEN; RASSF1; cfDNA; liquid biopsy; ovarian cancer; pyrosequencing.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Heat map of each CpG site methylation values in tissue (A) and plasma samples (B) according to diagnosis. OC—ovarian cancer; BC-OC—ovarian cancer subsequent to breast cancer.
Figure 2
Figure 2
Heat map of MI values in tissue (A) and plasma (B) samples according to diagnosis. MI—methylation index, OC—ovarian cancer; BC-OC—ovarian cancer subsequent to breast cancer.
Figure 3
Figure 3
The swarmplots of methylation indices of RASSF1, PTEN, CDH1 and PAX1 genes, showing the mean values of all observations. MI—methylation index; 0—control tissues (green squares); 1—benign tumours (blue triangles); 2—ovarian cancers (pink circles); 3—ovarian cancers subsequent to breast cancer (purple crossed circles).
Figure 4
Figure 4
Methylation indices of RASSF1, PTEN, CDH1 and PAX1 genes in paired tissue and plasma samples. MI—methylation index; C—control samples; B—benign; OC—ovarian cancer; BC-OC—ovarian cancer subsequent to breast cancer.
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