Tumor Specific Methylome in Chinese High-Grade Serous Ovarian Cancer Characterized by Gene Expression Profile and Tumor Genotype

Abstract

Background: Extensive genetic and limited epigenetics have been characterized by the Cancer Genome Atlas (TCGA) among Western High-grade serous ovarian cancer (HGSOC). However, Chinese HGSOC has not been characterized at genome scale. Methods: We used reduced representation bisulfite sequencing (RRBS) to investigate the whole-genome and tumor-specific DNA methylation in 21 HGSOC paired with their non-neoplastic normal tissues, followed by a replication study involving another 41 pairs of HGSOC tumor and normal tissues. Altered methylation patterns in HGSOC were further characterized by gene expression profiles and whole-exome sequencing data. Findings: The comparisons between HGSOC and normals revealed 159,881 differentially methylated regions (DMRs) and 4,060 differentially expressed genes (DEGs). By integrating DNA methylation and mRNA expression data, we identified 153 (mainly in the upstream region) and 115 genes (mainly in the CDS regions) with negative and positive correlation, respectively. Subsequently, 11 DMRs, accompanied with a global DNA methylation marker (1ong interspersed nuclear elements 1, LINE-1), were selected and validated in the independent replication samples. Whole-exome sequencing presented a different mutational landscape in Chinese HGSOC compared to TCGA dataset, with a relatively dominated TP53 mutation (52.3% vs 96%) and a less-frequently mutated BRCA1/2 (4.7% vs 22%). Unsupervised analysis of the three-level omics data of HGSOC identified differential methylation and expression subgroups based on tumor genetics, one of which presented increased DNA methylation and significantly associated with TP53 mutation. Interpretation: Our individual and integrated analyses contribute details about the tissue-specific genetic and DNA methylation landscape of HGSOC. Funding Statement: This work was supported by the National Key Research and Development Program of China (grant number: 2016YFC1302703), the National Natural Science Foundation of China (81320108022, 81502877, and 81973113), the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT) in China (IRT_14R40), Tianjin Science and Technology Committee Foundation (16JCYBJC26600 and 18YFZCSY00520), the American Cancer Society Research Professor Award. Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The Ethics Committee of Tianjin Medical University Cancer Institute and Hospital approved the study protocol, and written informed consent was obtained from all patients. This procedure was conducted in accordance with the approved guidelines.