Background/Objectives: Cirrhosis is the precursor to most cases of hepatocellular carcinoma (HCC). Understanding the mechanisms leading to the transition from cirrhosis to HCC and identifying key biomarkers is crucial to developing effective screening strategies and reducing HCC-related mortality. DNA methylation is associated with gene inactivation and plays an important role in physiological and pathological processes; however, its role in cirrhosis progression to HCC is unknown. Methods: We performed genome-wide DNA methylation profiling using Illumina Infinium MethylationEPI BeadChip in pre-diagnostic samples from 22 cirrhosis patients who subsequently developed HCC and 22 cirrhosis patients who remained HCC-free during an average 4-year follow-up. In a secondary analysis, we examined a subset of patients without hepatitis C virus (HCV) infection. Results: We identified three differentially methylated positions (DMPs) located inADAM12(cg13674437) andPSD3(cg06758847 and cg24595678) that show a strong association with HCC risk (lower median vs. higher median hazards ratio (HR): HRcg13674437= 0.34, 95% CI = 0.14–0.83; HRcg06758847= 4.89, 95% CI = 1.79–13.33; HRcg24595678= 11.19, 95% CI = 3.27–38.35). After excluding all HCV-active patients from our analysis, the HR for the DMPs remained significant. Conclusions: In conclusion, the findings in this study support the theory that buffy coat-derived DNA methylation markers could be used to identify biomarkers among cirrhosis patients at high risk for HCC before clinical symptoms appear. A further study with a large prospective cohort is required to validate these findings.
背景/目的：肝硬化是大多数肝细胞癌（HCC）发生的前期病变。理解从肝硬化进展为HCC的机制并识别关键生物标志物，对于制定有效的筛查策略和降低HCC相关死亡率至关重要。DNA甲基化与基因失活相关，在生理和病理过程中发挥重要作用；然而，其在肝硬化向HCC进展中的作用尚不明确。方法：我们使用Illumina Infinium MethylationEPI BeadChip芯片，对22例后续发展为HCC的肝硬化患者和22例在平均4年随访期间未发生HCC的肝硬化患者的诊断前样本进行了全基因组DNA甲基化谱分析。在二次分析中，我们检测了未感染丙型肝炎病毒（HCV）的患者亚组。结果：我们鉴定出位于ADAM12（cg13674437）和PSD3（cg06758847和cg24595678）的三个差异甲基化位点（DMPs），它们与HCC风险显著相关（较低中位数 vs. 较高中位数风险比（HR）：HRcg13674437 = 0.34，95% CI = 0.14–0.83；HRcg06758847 = 4.89，95% CI = 1.79–13.33；HRcg24595678 = 11.19，95% CI = 3.27–38.35）。在分析中排除所有HCV活动性患者后，这些DMPs的HR值仍然显著。结论：总之，本研究的结果支持这一理论，即来源于血沉棕黄层的DNA甲基化标志物可用于在临床症状出现前，识别肝硬化患者中HCC高风险人群的生物标志物。需要一项大型前瞻性队列研究来进一步验证这些发现。
肿瘤(癌症)患者之家