We aimed to identify the specific subset of tumor suppressor genes (TSGs) that are methylation-silenced during the earliest steps of hepatocarcinogenesis, and to further evaluate whether these genes can serve as predictive biomarkers of hepatocellular carcinoma (HCC) emergence. A total of 482 liver tissues including 177 pairs of HCCs and matched nontumor livers and 128 liver biopsies from chronic hepatitis C (CHC) patients were analyzed for quantitative methylation analysis in 24 TSG promoters and three MINT loci. The tumors were classified as early, less-progressed, and highly progressed HCCs using histology and radiological approaches. A subset of TSGs that harbored distinctly high levels of methylation in early HCCs were selected. Based on the methylation profiles of these genes, Kaplan-Meier analyses were performed to determine time-to-HCC occurrence in CHC patients. Subsequently, multivariate analysis was performed using age, gender, fibrosis stage, and number of methylated TSGs as covariates. Among TSGs analyzed, a subset of eight TSGs (HIC1, GSTP1, SOCS1, RASSF1, CDKN2A, APC, RUNX3, and PRDM2) demonstrated a distinct cluster by hierarchical clustering and receiver operating characteristic analyses. This subset of TSGs showed significantly higher methylation levels in the early HCCs (P < 0.0001). In the CHC patients, methylation frequencies in these TSGs were associated with shorter time-to-HCC occurrence (P < 0.0001), and number of methylated genes was an independent risk factor for HCC (hazard ratio = 5.21, 95% confidence interval = 2.25-11.76, P = 0.0002). Conclusion: Epigenetic inactivation of a subset of TSGs plays a critical role in the earliest steps of hepatocarcinogenesis. Furthermore, epigenetic inactivation of these genes in CHC provides a prognostic value for determining the risk for developing HCC later in life.
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