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Aberrant promoter methylation profiles and association with survival in patients with hepatocellular carcinoma

Authors Zhong D, Cen H

Received 18 November 2016

Accepted for publication 17 January 2017

Published 8 May 2017 Volume 2017:10 Pages 2501—2509

DOI https://doi.org/10.2147/OTT.S128058

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 3

Editor who approved publication: Prof. Dr. Geoffrey Pietersz

Dani Zhong, Hong Cen

Department of Chemotherapy, Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China

Abstract: The aim of this study was to investigate the prognostic and diagnostic value of genes with promoter methylation in hepatocellular carcinoma (HCC) patients. On the basis of The Cancer Genome Atlas data, we identified genes with differentially methylated promoters in HCC tissues and adjacent non-tumor tissues, using the linear models for microarray data approach. Cox proportional hazard regression analysis was applied to access the prognostic value of identified differentially methylated genes. The diagnostic value of the genes was evaluated through receiver operating characteristic. Pathway analyses were performed to illustrate biological functions of the identified genes. Compared to adjacent tissues, 77 genes with hypermethylated promoters and 2,412 genes with hypomethylated promoters were identified in HCC. The promoter hypomethylations of RNA5SP38, IL21, SDC4P, and MIR4439 were found to be associated with HCC patient survival (P=0.035, 0.040, 0.004, and 0.024, respectively). Hypomethylated SDC4P was associated with a better prognosis (hazard ratio, 0.482; 95% confidence interval [CI], -0.147–1.110; P=0.007). The combination of the promoter hypomethylations with RNA5SP38, IL21, and SDC4P showed an area under receiver operating characteristic curves of 0.975 (95% CI, 0.962–0.989; P=4.811E-25). Several pathways, including olfactory transduction, cytokine–cytokine receptor interaction, natural killer cell–mediated cytotoxicity, as well as inflammation mediated by chemokine and cytokine signaling pathway, were annotated with the hypomethylated promoter genes. SDC4P promoter hypomethylation may be a potential prognosis biomarker. A panel of promoter methylations in RNA5SP38, IL21, and SDC4P was proven a novel approach to diagnosis HCC. The pathway analysis defined the extensive functional role of DNA hypomethylation in cancer.

Keywords: hepatocellular carcinoma, promoter methylation, prognosis, diagnosis

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