Pan-cancer analysis of frequent DNA co-methylation patterns reveals consistent epigenetic landscape changes in multiple cancers

Jie Zhang,Kun Huang

doi:10.1186/s12864-016-3259-0

Abstract

BackgroundDNA methylation is the major form of epigenetic modifications through which the cell regulates the gene expression and silencing. There have been extensive studies on the roles of DNA methylation in cancers, and several cancer drugs were developed targeting this process. However, DNA co-methylation cluster has not been examined in depth, and co-methylation in multiple cancer types has never been studied previously.ResultsIn this study, we applied newly developed lmQCM algorithm to mine co-methylation clusters using methylome data from 11 cancer types in TCGA database, and found frequent co-methylated gene clusters exist in these cancer types. Among the four identified frequent clusters, two of them separate the tumor sample from normal sample in 10 out of 11 cancer types, which indicates that consistent epigenetic landscape changes exist in multiple cancer types.ConclusionThis discovery provides new insight on the epigenetic regulation in cancers and leads to potential new direction for epigenetic biomarker and cancer drug discovery. We also found that genes commonly believed to be silenced via hypermethylation in cancers may still display highly variable methylation levels among cancer cells, and should be considered while using them as epigenetic biomarkers.

Highlights

DNA methylation is the major form of epigenetic modifications through which the cell regulates the gene expression and silencing
The array platform difference has minimal effect on the identified co-methylation clusters for acute myeloid leukemia (AML), lung squamous cell carcinoma (LUSC), stomach adenocarcinoma (STAD) and uterine corpus endometrial carcinoma (UCEC) data, but it showed some discrepancies for glioblastoma multiforme (GBM)
By computing the Jaccard indices between every pair of cancer types coerced co-methylated clusters, we found that, in general, co-methylation clusters are mostly unique for Ovarian serous cystadenocarcinoma (OVCA) and AML; while digestive system cancers STAD, colon adenocarcinoma (COAD) and Liver hepatocellular carcinoma (LIHC) co-methylation clusters are more similar to each other (Fig. 1a)

Summary

Introduction

DNA methylation is the major form of epigenetic modifications through which the cell regulates the gene expression and silencing. There have been extensive studies on the roles of DNA methylation in cancers, and several cancer drugs were developed targeting this process. DNA methylation level regulates gene transcription activities and expression levels, exerting an important role in programming cell development and differentiation [1]. It is generally believed that in cancer cells tumor suppressor genes are hypermethylated in the promoter region and are repressed, while oncogenes are hypomethylated and abnormally active [8] Researchers applied this notion to cancer drug designs, and developed cancer drugs targeting DNA methyltransferases, The Author(s) BMC Genomics 2017, 18(Suppl 1):1045 attempting to correct the abnormal methylation pattern of tumor suppressors and oncogenes [9]. Quite a few genes have been associated with certain phenotypes (CpG island methylator phenotype, CIMP [7, 10, 11]) or identified as prognosis/diagnosis biomarkers in cancer due to the ease of detection and analysis in body fluid, and the events may happen in the early or premalignant stage of tumor development [1]

Methods

Results

Discussion

Conclusion