Abstract
Although great progress has been made in treatment against hepatitis virus infection, the prognosis of hepatocellular carcinoma (HCC) remains unsatisfied. Therefore, there is an unmet need to explore biomarkers or prognostic models for monitoring non-viral hepatocellular carcinoma. Accumulating evidence indicates that DNA methylation participates in carcinogenesis of malignancies. In the present study, we analyzed 101 non-viral HCC patients from TCGA database to figure out methylation-driven genes (MDGs) that might get involved in non-viral HCC pathogenesis using MethyMix algorithm. Then we picked out 8 key genes out of 137 MDGs that could affect the overall survival (OS) of both methylation and expression level. Using PCA, Uni-variate, Multi-variate, and LASSO cox regression analyses, we confirmed the potential prognostic value of these eight epigenetic genes. Ultimately, combined with immunohistochemistry (IHC), ROC, OS, and GSEA analyses, fat storage-inducing transmembrane protein1 (FITM1) was identified as a novel tumor suppressor gene in non-viral HCC and an applicable FITM1-methylation-based signature was built in a training set and validated in a testing set. Briefly, our work provides several potential biomarkers, especially FITM1, as well as a new method for disease surveillance and treatment strategy development.
Highlights
Hepatocellular carcinoma (HCC) is a highly malignant tumor with high mortality and brings a great burden to social economy (Siegel et al, 2017)
After downloading the comprehensive data of 101 non-viral hepatocellular carcinoma patients, the MethylMix algorithm mentioned above was adopted to figure out 137 methylation-driven genes (MDGs) in nonviral HCC (Figure 2A and Table S2)
Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that these 137 MDGs were significantly enriched in pathways in “Glutathione metabolism”, “Aldosterone-regulated sodium reabsorption”, “Fat digestion and absorption”, and “Cholesterol metabolism”, consistent with the result of Gene Ontology (GO) analysis. “p53 signaling pathway”, “HIF-1 signaling pathway”, and “EGFR tyrosine kinase inhibitor resistance” were enriched, suggesting the potential regulating signaling pathway of nonviral HCC by MDGs (Figure 2C)
Summary
Hepatocellular carcinoma (HCC) is a highly malignant tumor with high mortality and brings a great burden to social economy (Siegel et al, 2017). Commonly hepatitis B virus (HBV) and hepatitis C virus (HCV), and long-term alcohol consumption are the major etiology of HCC development (Braillon, 2012). Viral hepatitis infection is strongly responsible for liver cancer progression, various non-viral risk factors play important roles in promoting HCC development (Alzahrani et al, 2014). There is an unmet need to understand the underlying molecular mechanism of non-viral HCC. Due to the high heterogeneity and molecular diversities (Bruix et al, 2014), the prognosis of non-viral HCC patients is widely divergent. An effective and accurate model to predict the prognosis of non-viral HCC individually is important and helpful to inform future clinical-decision making
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