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

SIMPLE SUMMARY: It is widely accepted that DNA methylation, mediated by DNA methyltransferases, is altered in epithelial ovarian cancer (EOC) and contributes to carcinogenesis, the advancement of the disease and even its chemotherapy resistance. After an immunohistochemical study of a patient cohort from our department and TNM plot, GEPIA2, Kaplan–Meier Plotter, TCGA and Proteomic data analysis for mRNA and protein expression of DNMTs (DNMTA, DNMT2, DNMT3A, DNMT3B and DNMT3L), it is obvious that DNMTs expression is altered in ovarian cancer tissues. DNMT1, DNMT3A, DNMT3B and DNMT3L are overexpressed in primary high-grade EOC. DNMT3A is overexpressed in the early stages only, whereas DNMT1 and DNMT3L are also overexpressed in tumor relapses. On the other hand, DNMT2 is downregulated in high-grade ovarian carcinomas. This can be a pivotal first step in biomarker and/or more effective targeted treatment development for patients with ovarian cancer. 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.