Integrated analysis of DNA methylation profiling and gene expression profiling identifies novel markers in lung cancer in Xuanwei, China.

Juan Wang,Yong Duan,Yanliang Zhang,Qing-He Meng,Rong Gong,Chong Guo,Ying Zhao,Qian Tao

doi:10.1371/journal.pone.0203155

Abstract

BackgroundAberrant DNA methylation occurs frequently in cancer. The aim of this study was to identify novel methylation markers in lung cancer in Xuanwei, China, through integrated genome-wide DNA methylation and gene expression studies.MethodsDifferentially methylated regions (DMRs) and differentially expressed genes (DEGs) were detected on 10 paired lung cancer tissues and noncancerous lung tissues by methylated DNA immunoprecipitation combined with microarray (MeDIP-chip) and gene expression microarray analyses, respectively. Integrated analysis of DMRs and DEGs was performed to screen out candidate methylation-related genes. Both methylation and expression changes of the candidate genes were further validated and analyzed.ResultsCompared with normal lung tissues, lung cancer tissues expressed a total of 6,899 DMRs, including 5,788 hypermethylated regions and 1,111 hypomethylated regions. Integrated analysis of DMRs and DEGs identified 45 tumor-specific candidate genes: 38 genes whose DMRs were hypermethylated and expression was downregulated, and 7 genes whose DMRs were hypomethylated and expression was upregulated. The methylation and expression validation results identified 4 candidate genes (STXBP6, BCL6B, FZD10, and HSPB6) that were significantly hypermethylated and downregulated in most of the tumor tissues compared with the noncancerous lung tissues.ConclusionsThis integrated analysis of genome-wide DNA methylation and gene expression in lung cancer in Xuanwei revealed several genes regulated by promoter methylation that have not been described in lung cancer before. These results provide new insight into the carcinogenesis of lung cancer in Xuanwei and represent promising new diagnostic and therapeutic targets.

Highlights

Lung cancer is the fastest-increasing cancer in China and, since 2004, the leading cause of cancer death [1]
This integrated analysis of genome-wide DNA methylation and gene expression in lung cancer in Xuanwei revealed several genes regulated by promoter methylation that have not been described in lung cancer before
MeDIP-chip analysis of genome-wide DNA methylation on paired lung cancer and normal lung tissues found that, compared with the normal tissues, the tumor tissues had a total of 6,899 Differentially methylated regions (DMRs), including 5,788 hypermethylated regions and 1,111 hypomethylated regions (the microarray data has uploaded to Gene Expression Omnibus (GEO), the relevant accession number is GSE113432)

Summary

Introduction

Lung cancer is the fastest-increasing cancer in China and, since 2004, the leading cause of cancer death [1]. Lung cancer in Xuanwei has other unique characteristics [1, 3, 5]: the incidence and mortality vary significantly among various regions; the incidence is high in women, who are mostly nonsmokers, and is the highest for women in the entire country of China; the ratio of lung cancer mortality of males and females (1.09) is significantly lower than the national average (2.09); lung cancer incidence peaks at a younger age (41–50), more than 10 years younger than in other areas of the country; and adenocarcinoma is the major type It is account for 60.6% in one study [6] and 53.3% [7] in another study. The aim of this study was to identify novel methylation markers in lung cancer in Xuanwei, China, through integrated genomewide DNA methylation and gene expression studies

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