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

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.

Tumor specific methylome in Chinese high-grade serous ovarian cancer characterized by gene expression profile and tumor genotype

“…Of note, only about 13% of the genes met the assumed gene expression results correlated to their methylation status. Reyes et al [11] reported a 17-33% of the genes showing inverse relationships between methylation status and gene expression, although their study is different from ours. Even in TCGA HGSOC dataset, a hypermethylation directing down-regulation of gene expression was observed only in 168 out of 14,475 probed genes [6].…”

“…When compared to the more hypermethylated DMRs in promoter and cds region, a higher percent of hypomethylated DMRs was observed located in the wide ranges of unclearly annotated regions with potentially unknown functions [26]. Two recent genome-wide methylomic analysis to screen for differential methylation sites occurring in HGSOC in comparison with unpaired normal fallopian tubes, consistently demonstrated a preponderance of cancer-specific DMRs located outside CGIs regions, rather in the CpG shores, shelves and open sea regions [10,11].…”

“…With the development of higher resolution methylation arrays (Illumina's Human Methylation 27 K, 450 K and the newest 850 K) in the past dozen years, studies with larger sample numbers and including non-individual matching normal tissue have profiled the methylome [3,[8][9][10] or multi-omics [4,6,11] of HGSOC, among which The Cancer Genome Atlas (TCGA) surveyed 489 HGSOC and 8 fallopian tube samples and found 168 aberrantly hypermethylated genes with reduced gene expression [6]. Only five of these genes overlapped with 543 hypermethylated genes identified in another analysis of chemoresistant HGSOC using 450 K Methylation Array [4].…”

“…Only five of these genes overlapped with 543 hypermethylated genes identified in another analysis of chemoresistant HGSOC using 450 K Methylation Array [4]. The recent two genomewide methylation analysis (by current generation chip 850 K) have focused on addressing epigenomic phenomena that contribute to the biological heterogeneity, early-stage detecting and behavior of ovarian cancer [10,11]. Variations in the sample size, consideration of normal controls, and statistical analysis techniques for microarray data may account for the relatively low consistency of results [1,12].…”

Identification of Novel lncRNAs in Ovarian Cancer and Their Impact on Overall Survival

“…Of those, 12 produced viable RNA for analysis. RNA from both the fallopian tube and HGSC specimens had already been extracted and purified in a previous study [ 25 ].…”