An Integrated Approach to Uncover Driver Genes in Breast Cancer Methylation Genomes

Xiaopei Shen,Wenjing Zhang,Lin Zhang,Tongwei Shi,Chunyang Liu,Xianxiao Zhou,Tingting Zheng,Chunxiang Hao,Zheng Guo,Shan Li,Hongdong Li,Guini Hong,Christina Chan

doi:10.1371/journal.pone.0061214

Xiaopei Shen, Wenjing Zhang + Show 11 more

Open Access

https://doi.org/10.1371/journal.pone.0061214

Copy DOI

Abstract

BackgroundCancer cells typically exhibit large-scale aberrant methylation of gene promoters. Some of the genes with promoter methylation alterations play “driver” roles in tumorigenesis, whereas others are only “passengers”.ResultsBased on the assumption that promoter methylation alteration of a driver gene may lead to expression alternation of a set of genes associated with cancer pathways, we developed a computational framework for integrating promoter methylation and gene expression data to identify driver methylation aberrations of cancer. Applying this approach to breast cancer data, we identified many novel cancer driver genes and found that some of the identified driver genes were subtype-specific for basal-like, luminal-A and HER2+ subtypes of breast cancer.ConclusionThe proposed framework proved effective in identifying cancer driver genes from genome-wide gene methylation and expression data of cancer. These results may provide new molecular targets for potential targeted and selective epigenetic therapy.

Highlights

Abnormality in DNA methylation plays an important role in cancer initiation and progression
It is difficult to discriminate the drivers from the passengers [6] in a large number of genes differentially methylated in human cancer genomes [4], and the identification of driver genes with methylation alterations is a fundamental step towards molecular characterization of cancer
From these 888 loci, we found 350 loci from 311 genes which influenced the expression alterations of significantly more downstream genes than expected by random chance according to the random experiments described in the Methods

Summary

Introduction

Abnormality in DNA methylation plays an important role in cancer initiation and progression. Only a small portion of these genes play ‘‘driver’’ roles in cancer initiation and progression, while the others are only ‘‘passengers’’ in the tumorigenic process [5,6]. Using genome-wide methylation data, De Carvalho developed an approach to identify a specific type of driver genes for the survival of cancer cells [5]. There are evidences that promoter hypomethylation of some genes may be associated with the initiation and progression of cancer by regulating the activity of the genes [7,8,9]. Some of the genes with promoter methylation alterations play ‘‘driver’’ roles in tumorigenesis, whereas others are only ‘‘passengers’’

Methods

Results

Conclusion