Dani Zhong, Hong Cen

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.