Huang Yiwen, Chen Guangpeng, Fan Hong, Wang Shangzi, Yuan Huangbo, Liu Zhengqiu, Zhang Tiejun
Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China.
Taizhou Institute of Health Sciences, Taizhou, China.
Transl Cancer Res. 2025 Jul 30;14(7):4243-4259. doi: 10.21037/tcr-2024-2607. Epub 2025 Jul 23.
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.
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.
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.
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.
乙型肝炎病毒相关肝细胞癌（HBV-HCC）和丙型肝炎病毒相关肝细胞癌（HCV-HCC）之间的遗传和表观遗传差异仍未得到充分研究。本研究旨在通过一种创新方法从比较的角度阐明HBV-HCC和HCV-HCC的DNA甲基化模式及特征。
我们基于癌症基因组图谱（TCGA）数据库进行基因表达和甲基化分析，以鉴定差异表达基因（DEGs）和差异甲基化探针（DMPs）。采用Cox生存分析来鉴定与预后相关的DEGs（Pro-DEGs）。使用一种新颖的序列最小绝对收缩和选择算子（Seq-Lasso）技术整合基因表达和DNA甲基化数据，随后生成基因水平的DNA甲基化汇总。这些汇总分别用于从HBV-HCC和HCV-HCC的Pro-DEGs中选择甲基化-表达定量性状位点（methyl-eQTLs）。
无论基因组区域如何，低甲基化在HBV-HCC中比在HCV-HCC中更普遍。值得注意的是，HBV-HCC患者组的开放海域区域含有功能上最显著的甲基化位点，而在HCV-HCC患者组中，当与基因内的基因表达呈正相关时，功能上最重要的胞嘧啶-磷酸-鸟嘌呤（CpG）位点通常位于陆架区域。我们进一步构建并验证了一个基于与HCC预后相关的六个甲基化-eQTLs的预后指数（PI）。
我们的研究发现，CpG岛位点在HBV-HCC和HCV-HCC中功能重要性最低。并且，我们还构建并验证了一个基于六个甲基化-eQTLs的PI，其可能通过RFC3与HCC预后相关。
