Differential DNA methylation in high-grade serous ovarian cancer (HGSOC) is associated with tumor behavior

Henry D Reyes,Eric J Devor,Andreea M Newtson,Vincent Wagner,Akshaya Warrier,Gabrielle N Duncan,Jordan Mattson,Kimberly K Leslie,Jesus Gonzalez-Bosquet

doi:10.1038/s41598-019-54401-w

Abstract

The epigenome offers an additional facet of cancer that can help categorize patients into those at risk of disease, recurrence, or treatment failure. We conducted a retrospective, nested, case-control study of advanced and recurrent high-grade serous ovarian cancer (HGSOC) patients in which we assessed epigenome-wide association using Illumina methylationEPIC arrays to characterize DNA methylation status and RNAseq to evaluate gene expression. Comparing HGSOC tumors with normal fallopian tube tissues we observe global hypomethylation but with skewing towards hypermethylation when interrogating gene promoters. In total, 5,852 gene interrogating probes revealed significantly different methylation. Within HGSOC, 57 probes highlighting 17 genes displayed significant differential DNA methylation between primary and recurrent disease. Between optimal vs suboptimal surgical outcomes 99 probes displayed significantly different methylation but only 29 genes showed an inverse correlation between methylation status and gene expression. Overall, differentially methylated genes point to several pathways including RAS as well as hippo signaling in normal vs primary HGSOC; valine, leucine, and isoleucine degradation and endocytosis in primary vs recurrent HGSOC; and pathways containing immune driver genes in optimal vs suboptimal surgical outcomes. Thus, differential DNA methylation identified numerous genes that could serve as potential biomarkers and/or therapeutic targets in HGSOC.

Highlights

Ovarian cancer is the fifth leading cause of death in women and is responsible for more deaths than any other gynecologic malignancy, with an estimated 22,530 new cases and 13,980 related deaths in the US for 20191,2
When the genes represented by the probes that are different between the controls and high-grade serous ovarian cancer (HGSOC) are plugged in to the Kyoto Encyclopedia of Genes and Genomes (KEGG) wiring diagram database where genes are integrated into a pathway map and analyzed, several pathways are noted to be enriched, such as the RAS, dopaminergic synapse, Adherens junction, and Hippo signaling pathways
When considering global methylation status detected by long-range CpG probes that include CpG sites in both island and open sea regions[28], there is nearly universal hypomethylation in HGSOC compared with fallopian tube controls (Fig. 5A)

Summary

Introduction

Ovarian cancer is the fifth leading cause of death in women and is responsible for more deaths than any other gynecologic malignancy, with an estimated 22,530 new cases and 13,980 related deaths in the US for 20191,2. The objectives of our study are: (1) to assess differential DNA methylation globally between high grade serous ovarian tumors and normal fallopian tube controls; (2) to examine methylation status differences within HGSOC relative to important clinical outcomes such as recurrence and debulking status; and (3) to correlate methylation status with RNA expression. These data will further characterize epigenomic phenomena that contribute to heterogeneity in the biology and behavior of ovarian cancer and inform future therapeutic decision making

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Conclusion