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. 2018 Sep 17:18:140.
doi: 10.1186/s12935-018-0629-5. eCollection 2018.

DNA methylation biomarkers for hepatocellular carcinoma

Guorun Fan #  1 , Yaqin Tu #  1 , Cai Chen  2 , Haiying Sun  1 , Chidan Wan  3 , Xiong Cai  3
Affiliations

DNA methylation biomarkers for hepatocellular carcinoma

Guorun Fan et al. Cancer Cell Int. .

Abstract

Background: Aberrant methylation of DNA is a key driver of hepatocellular carcinoma (HCC). In this study, we sought to integrate four cohorts profile datasets to identify such abnormally methylated genes and pathways associated with HCC.

Methods: To this end, we downloaded microarray datasets examining gene expression (GSE84402, GSE46408) and gene methylation (GSE73003, GSE57956) from the GEO database. Abnormally methylated differentially expressed genes (DEGs) were sorted and pathways were analyzed. The String database was then used to perform enrichment and functional analysis of identified pathways and genes. Cytoscape software was used to create a protein-protein interaction network, and MCODE was used for module analysis. Finally, overall survival analysis of hub genes was performed by the OncoLnc online tool.

Results: In total, we identified 19 hypomethylated highly expressed genes and 14 hypermethylated lowly expressed genes at the screening step, and finally found six mostly changed hub genes including MAD2L1, CDC20, CCNB1, CCND1, AR and ESR1. Pathway analysis showed that aberrantly methylated-DEGs mainly associated with the cell cycle process, p53 signaling, and MAPK signaling in HCC. After validation in TCGA database, the methylation and expression status of hub genes was significantly altered and same with our results. Patients with high expression of MAD2L1, CDC20 and CCNB1 and low expression of CCND1, AR, and ESR1 was associated with shorter overall survival.

Conclusions: Taken together, we have identified novel aberrantly methylated genes and pathways linked to HCC, potentially offering novel insights into the molecular mechanisms governing HCC progression and serving as novel biomarkers for precision diagnosis and disease treatment.

Keywords: Hepatocellular carcinoma; Hub genes; Methylation.

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Figures

Fig. 1
Fig. 1
The flowchart of this study
Fig. 2
Fig. 2
Identification of aberrantly methylated and differentially expressed genes was analyzed by Funrich software. Different color areas represented different datasets. a Hypomethylation and high expression genes; b hypermethylation and low expression genes
Fig. 3
Fig. 3
The heat map of 19 hypomethylation/high-expression genes and 14 hypermethylation/low-expression genes in GSE84402
Fig. 4
Fig. 4
PPI network and hub genes of aberrantly methylated and differentially expressed genes. a PPI network and b Hub genes for hypomethylation/high-expression genes; c PPI network and d hub genes of hypermethylation/low-expression genes
Fig. 5
Fig. 5
Core modules for aberrantly methylated and differentially expressed genes. Hypomethylation/high-expression genes a Module 1 and b the enrichment and pathways analysis of module 1; Hypermethylation/low-expression genes: c Module 1 and d the enrichment and pathways analysis of module 1; e Module 2 and f the enrichment and pathways analysis of module 2
Fig. 6
Fig. 6
Validation of the expression of hub genes in Oncomine database. The expression level of a MAD2L1, b CDC20, c CCNB1, d CCND1, e AR, and f ESR1 were detected in Oncomine database. Red: Hypomethylation/high-expression genes; Green: Hypermethylation/low-expression genes
Fig. 7
Fig. 7
Prognostic value of six hub genes in hepatocellular carcinoma. Prognostic value of a MAD2L1, b CDC20, c CCNB1, d CCND1, e AR, and f ESR1 were obtained in OncoLnc database. The survival curve comparing the patients with high (red) and low (blue) expression in HCC
See this image and copyright information in PMC

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