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

OBJECTIVE

Extensive genetic and limited epigenetics have been characterized by the Cancer Genome Atlas (TCGA) among Western High-grade serous ovarian cancer (HGSOC). The present study aimed to characterize Chinese HGSOC at genome scale.

METHODS

We used reduced representation bisulfite sequencing to investigate whole-genome and tumor-specific DNA methylation in 21 HGSOC tumors paired with their normal tissues, followed by a replication study involving additional 41 HGSOC patients. Altered methylation patterns in HGSOC were further characterized by gene expression profiles and whole-exome sequencing data.

RESULTS

Comparing HGSOC tumors with normal tissues we observed global hypomethylation but with more specific hypermethylation in gene promoter. Totally, we revealed 159,881 differentially methylated regions (DMRs) and 4060 differentially expressed genes (DEGs). By integrating DNA methylation and mRNA expression data, we identified 153 negative (mainly in the upstream region) and 115 positive (mainly in the CDS regions) DMRs-DEGs correlated pairs, respectively. The negatively correlated DMRs-DEGs underlined Wnt and cell adhesion molecule binding as critical canonical pathways disrupted by DNA methylation. Eleven DMRs (in CAPS, FZD7, CDKN2A, PON3, KLF4, etc.), accompanied with a global DNA methylation marker, were validated in the replication samples. Whole-exome sequencing presented a relatively less dominated TP53 mutation in Chinese HGSOC compared to TCGA dataset. Unsupervised analysis of the three-level omics data identified differential methylation and expression subgroups based on tumor genetics, one of which presented increased DNA methylation and significantly associated with TP53 mutation.

CONCLUSIONS

Our individual and integrated analyses contribute details about the tissue-specific genetic and DNA methylation landscape of Chinese HGSOC.