Comprehensive Analysis of DNA Methyltransferases Expression in Primary and Relapsed Ovarian Carcinoma

Efthymia Papakonstantinou; Ioanna Pappa; Georgios Androutsopoulos; Georgios Adonakis; Ioannis Maroulis; Vasiliki Tzelepi

doi:10.3390/cancers15204950

Comprehensive Analysis of DNA Methyltransferases Expression in Primary and Relapsed Ovarian Carcinoma

Cancers (Basel). 2023 Oct 11;15(20):4950. doi: 10.3390/cancers15204950.

Authors

Efthymia Papakonstantinou¹, Ioanna Pappa², Georgios Androutsopoulos³, Georgios Adonakis¹, Ioannis Maroulis⁴, Vasiliki Tzelepi⁵

Affiliations

¹ Department of Obstetrics and Gynecology, School of Medicine, University of Patras, 26504 Patras, Greece.
² Multidimensional Data Analysis and Knowledge Management Laboratory, Computer Engineering and Informatics Department, School of Engineering, University of Patras, 26504 Patras, Greece.
³ Gynecological Oncology Unit, Department of Obstetrics and Gynecology, Medical School, University of Patras, 26504 Patras, Greece.
⁴ Department of General Surgery, School of Medicine, University of Patras, 26504 Patras, Greece.
⁵ Department of Pathology, School of Medicine, University of Patras, 26504 Patras, Greece.

Abstract

Background: Despite recent advances in epithelial ovarian carcinoma (EOC) treatment, its recurrence and mortality rates have not improved significantly. DNA hypermethylation has generally been associated with an ominous prognosis and chemotherapy resistance, but the role of DNA methyltransferases (DNMTs) in EOC remains to be investigated.

Methods: In the current study, we systematically retrieved gene expression data from patients with EOC and studied the immunohistochemical expression of DNMTs in 108 primary and 26 relapsed tumors.

Results: Our results showed that the DNMT1, DNMT3A, DNMT3B and DNMT3L RNA levels were higher and the DNMT2 level was lower in tumors compared to non-neoplastic tissue, and DNMT3A and DNMT2 expression decreased from Stage-II to Stage-IV carcinomas. The proteomic data also suggested that the DNMT1 and DNMT3A levels were increased in the tumors. Similarly, the DNMT1, DNMT3A and DNMT3L protein levels were overexpressed and DNMT2 expression was reduced in high-grade carcinomas compared to non-neoplastic tissue and low-grade tumors. Moreover, DNMT1 and DNMT3L were increased in relapsed tumors compared to their primaries. The DNMT3A, DNMT1 and DNMT3B mRNA levels were correlated with overall survival.

Conclusions: Our study demonstrates that DNMT1 and DNMT3L are upregulated in primary high-grade EOC and further increase in relapses, whereas DNMT3A is upregulated only in the earlier stages of cancer progression. DNMT2 downregulation highlights the presumed tumor-suppressor activity of this gene in ovarian carcinoma.

Keywords: DNA methylation; DNA methyltransferases; DNMT; high-grade ovarian cancer; ovarian cancer; relapsed ovarian cancer.

Grants and funding

This research was funded by the Research Committee of the University of Patras via the “K. Karatheodori” program (N: 56570000) and the BBMRI-GR: Infrastructure for Biobanking and Biomolecular Resources in Health and Life Sciences, (MIS 5028275) implemented under the Action “Reinforcement of the Research and Innovation Infrastructure”, funded by the Operational Program “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014-2020) and co-financed by Greece and the European Union (European Regional Development Fund). The publication fees of the manuscript have been financed by the Research Council of the University of Patras.