Methylomic Signatures of High Grade Serous Ovarian Cancer

ABSTRACT

High-grade serous ovarian cancer (HGSOC) harbours aberrant epigenetic features, including DNA methylation. In this study we delineate pathways and networks altered by DNA methylation and associated with HGSOC initiation and progression to a platinum-resistant state. By including tumours from patients who had been treated with the hypomethylating agent (HMA) guadecitabine, we also addressed the role of HMAs in treatment of HGSOC. Tumours from patients with primary (platinum-naïve) HGSOC (n = 20) were compared to patients with recurrent platinum-resistant HGSOC and enrolled in a recently completed clinical trial (NCT01696032). Human ovarian surface epithelial cells (HOSE; n = 5 samples) served as normal controls. Genome-wide methylation profiles were determined. DNA methyltransferase (DNMT) expression levels were examined by immunohistochemistry and correlated with clinical outcomes. Cancer-related and tumorigenesis networks were enriched among differentially methylated genes (DMGs) in primary OC vs. HOSE. When comparing platinum-resistant and primary tumours, 452 CpG island (CGI)-containing gene promoters acquired DNA methylation; of those loci, decreased (P < 0.01) methylation after HMA treatment was observed in 42% (n = 189 CGI). Stem cell pluripotency and cytokine networks were enriched in recurrent platinum-resistant OC tumours, while drug metabolism and transport-related networks were downregulated in tumours from HMA-treated patients compared to HOSE. Lower DNMT1 and 3B protein levels in pre-treatment tumours were associated with improved progression-free survival. The findings provide important insight into the DNA methylation landscape of HGSOC tumorigenesis, platinum resistance and epigenetic resensitization. Epigenetic reprogramming plays an important role in HGSOC aetiology and contributes to clinical outcomes.

KEYWORDS:

• Ovarian cancer
• epigenetics
• methylation
• platinum
• resistance

Acknowledgments

We thank the Genomics Facility of The University of Chicago for help with Illumina HumanMethylation450 BeadChip. We thank Dr. Theresa Woodruff (Northwestern University) for providing the normal fallopian tube epithelial cells. This work was funded in part by the National Cancer Institute Award CA182832-01 and a V Foundation Translational Grant (to DM and KPN).

Authors’ contributions

HC and FF: acquisition, analysis and interpretation of the data, writing original draft. GJ: data curation, software, formal analysis. SMP: data curation, software, formal analysis. CZ: data curation, software, formal analysis. HNK: investigation, resources. YL: data curation, software, formal analysis. KNP and DM: conceived the idea, supervised research personnel and interpreted data. All authors read, critically reviewed and approved the final manuscript.

Disclosure statement

The authors declare that they have no competing interests.

Data availability statement

Illumina HumanMethylation450 BeadChip results are available for download at Gene Expression Omnibus (GEO) data repository at the National Center for Biotechnology Information (NCBI) under the accession number GSE102119.

Ethics approval and consent to participate

All protocols and procedures for human subjects were approved by Indiana University School of Medicine.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This work was supported by the National Cancer Institute Award CA182832-01 and the V- Foundation (to D.M. and K.P.N).