Global methylation profiling in serous ovarian cancer is indicative for distinct aberrant DNA methylation signatures associated with tumor aggressiveness and disease progression

Abstract

Objective: To characterize at high resolution the DNA methylation changes which occur in the genome of serous epithelial ovarian cancer (EOC) in association with tumor aggressiveness.

Methods: Methylated DNA immunoprecipitation in combination with CpG island-tiling arrays was used to compare the methylation profiles of five borderline, five grade 1/stage III/IV, five grade 3/stage I and five grade 3/stage III/IV serous EOC tumors, to those of five normal human ovarian tissue samples.

Results: We found widespread DNA hypermethylation that occurs even in low-malignant potential (borderline) tumors and which predominantly includes key developmental/homeobox genes. Contrary to DNA hypermethylation, significant DNA hypomethylation was observed only in grade 3 serous EOC tumors. The latter observation was further confirmed when comparing the DNA methylation profiles of primary cell cultures derived from matched tumor samples obtained prior to, and following chemotherapy treatment from two serous EOC patients with advanced disease. To our knowledge this is the first report that has shown the presence of massive DNA hypomethylation in advanced serous EOC, associated with tumor malignancy and disease progression.

Conclusions: Our data raise the concern that demethylating drugs that are currently being used in advanced EOC disease (representing the majority of serous EOC cases) might have adverse effects due to activation of oncogenes and prometastatic genes. Understanding the relative roles of hypomethylation and hypermethylation in cancer could have clear implications on the therapeutic use of agents targeting the DNA methylation machinery.