Abstract
BACKGROUND: The genetic and epigenetic differences between hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) and hepatitis C virus-related hepatocellular carcinoma (HCV-HCC) remain underexplored. This study aimed to elucidate DNA methylation patterns and features of HBV-HCC and HCV-HCC through use of an innovative method from a comparative perspective. METHODS: We conducted gene expression and methylation analyses to identify differentially expressed genes (DEGs) and differentially methylated probes (DMPs) based on The Cancer Genome Atlas (TCGA) database. Cox survival analysis was employed to identify prognosis-related DEGs (Pro-DEGs). A novel sequential least absolute shrinkage and selection operator (Seq-Lasso) technique was used to integrate gene expression and DNA methylation data, subsequently generating gene-level DNA methylation summaries. These summaries were used to select methylation-expression quantitative trait loci (methyl-eQTLs) from Pro-DEGs for HBV-HCC and HCV-HCC, respectively. RESULTS: Hypomethylation was more prevalent in HBV-HCC than in HCV-HCC in regardless of the genome region. Notably, open sea regions of the HBV-HCC patient group contained the most functionally significant methylation sites, whereas in the HCV-HCC patient group, the most functionally important cytosine-phosphate-guanine (CpG) sites were typically located in shelf regions when positively associated with gene expression within genes. We further constructed and validated a prognostic index (PI) based on six methyl-eQTLs associated with HCC prognosis. CONCLUSIONS: Our study found that CpG island sites had the least functional importance in both HBV-HCC and HCV-HCC. And, we also constructed and validated a PI based on six methyl-eQTLs that may be related to HCC prognosis via RFC3.