Role of m5C-related regulatory genes in the diagnosis and prognosis of hepatocellular carcinoma.

: Hepatocellular carcinoma (HCC) is one of the most common malignancies globally, and is frequently associated with a poor prognosis. 5-methylcytosine (m5C) is a common epigenetic modification with many critical roles in eukaryotes. However, the expression and functional roles of m5C regulators are largely unknown. In this study, we utilized The Cancer Genome Atlas (TCGA) to determine the expression, gene signatures, and prognostic values of m5C-related genes. We confirmed that the frequency of mutation events of m5C regulatory genes was high in HCC (35/363). Dysregulation of m5C-related genes was also associated with a higher HCC stage. Moreover, a strong relationship was found between the expression of m5C regulatory genes and HCC patient survival. High expression of NSUN4 and ALYREF correlated significantly with survival outcome. We developed a two-gene signature of m5C regulators with HCC prognostic value based on the least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression models. Gene set enrichment analysis (GSEA) results indicated that high expression of NSUN4 was associated with methylation and demethylation processes. Meanwhile, high expression of ALYREF was clearly related to cell cycle regulation and mitosis. In conclusion, our results revealed that m5C-related genes play an essential role in tumor progression in HCC. Further detection of m5C methylation could provide a novel method for HCC targeted therapy.