DNA methylation-based profiling reveals distinct clusters with survival heterogeneity in high-grade serous ovarian cancer

Jieyu Wang,Xin Lu,Wenzhi Li,Beibei Wu,Yang Bai,Huiran Yue,Ruifang Chen,Jun Li,Guohua Zhu

doi:10.1186/s13148-021-01178-3

Abstract

High-grade serous ovarian cancer (HGSOC) is the most common type of epigenetically heterogeneous ovarian cancer. Methylation typing has previously been used in many tumour types but not in HGSOC. Methylation typing in HGSOC may promote the development of personalized care. The present study used DNA methylation data from The Cancer Genome Atlas database and identified four unique methylation subtypes of HGSOC. With the poorest prognosis and high frequency of residual tumours, cluster 4 featured hypermethylation of a panel of genes, which indicates that demethylation agents may be tested in this group and that neoadjuvant chemotherapy may be used to reduce the possibility of residual lesions. Cluster 1 and cluster 2 were significantly associated with metastasis genes and metabolic disorders, respectively. Two feature CpG sites, cg24673765 and cg25574024, were obtained through Cox proportional hazards model analysis of the CpG sites. Based on the methylation level of the two CpG sites, the samples were classified into high- and low-risk groups to identify the prognostic information. Similar results were obtained in the validation set. Taken together, these results explain the epigenetic heterogeneity of HGSOC and provide guidance to clinicians for the prognosis of HGSOC based on DNA methylation sites.

Highlights

Epithelial ovarian cancer (EOC) has the highest fatality rate of female reproductive cancers [1], primarily because more than 70% of EOCs are diagnosed at advanced stages and are associated with disseminated intraperitoneal disease [2]
The prognostic model distinguished the training data sets and the validation sets into different prognosis clusters. This clinically promising model may be used to predict the prognosis of high-grade serous ovarian cancer (HGSOC) patients, and follow-up may be strengthened for high-risk patients. The results of this exploratory study suggest four distinct HGSOC clusters that are distinguishable with DNA methylation profiling and highlight several important genetic characteristics
We showed that the metabolism subtype had a favourable prognosis and that the hypermethylation subtype had the worst prognosis

Summary

Introduction

Epithelial ovarian cancer (EOC) has the highest fatality rate of female reproductive cancers [1], primarily because more than 70% of EOCs are diagnosed at advanced stages and are associated with disseminated intraperitoneal disease [2]. EOC is a heterogeneous disease that includes several subtypes with different clinical and molecular features [3]. The most prevalent histotype of EOC is high-grade serous ovarian cancer (HGSOC), which is associated with a poor prognosis. DNA methylation is a core type of epigenetic alterations and a key epigenetic regulator of gene expression associated with different tumour types [7]. Novel methods for tumour classification have been examined in recent years based on genome-wide DNA methylation data [10, 11]. There is increasing interest in the role of DNA methylation in defining molecular subtypes to assist in elucidating the clinical characteristics and prognosis of EOC [17,18,19]. Previous researches on the methylation of HGSOC are limited to appointed methylation sites or

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