Background/Objectives: The post-hepatectomy survival of patients with hepatocellular carcinoma (HCC) faces challenges due to high recurrence rates, especially early recurrence (ER). We investigated DNA methylation in HCC and developed a methylation-based model for ER prediction (MER). Methods: We studied HCC patients with ER within a year post-hepatectomy, comparing them to those who remained recurrence-free (RF) for 5 years. In a testing set, we examined genome-wide methylation profiles to identify differences between ER and RF. Validation in an independent cohort confirmed candidate markers using real-time quantitative methylation-specific PCR (qMSP). We constructed MER by incorporating identified gene methylation, clinical information, and serum protein marker, and evaluated its predictive performance using ROC analysis and Cox regression. Results: Distinct signatures of hypermethylation and hypomethylation were observed between ER and RF, as well as between cirrhotic and non-cirrhotic groups. Significant aberrant methylation pathways, including FGFR signaling, the PI3K network, and the MAPK pathway, were observed in non-cirrhotic ER patients. Conversely, cirrhotic ER patients showed notable associations with Wnt/β-catenin signaling, cell adhesion, and migration mechanisms. Through qMSP analysis, we identified ER-associated genes, including BDNF, FOXL2, LMO7, NCAM1, NEIS3, PLA2G7, and LTB4R. MER demonstrated strong predictive ability for ER, with an AUC of 0.855, surpassing current indicators such as AFP, tumor size, and BCLC stage. Combining different predictors resulted in heightened AUC values. Importantly, the inclusion of MER yielded to the highest AUC of 0.952, underscoring the substantial contribution of MER to predictive accuracy. Conclusions: This study discovered the involvement of aberrant DNA methylation in HCC with early recurrence. The MER outperforms clinicopathological predictors and achieves robust prediction capabilities in identifying patients at risk of ER.
背景/目的：肝细胞癌（HCC）患者肝切除术后生存面临高复发率，尤其是早期复发（ER）的挑战。本研究探讨了HCC中的DNA甲基化，并开发了一种基于甲基化的ER预测模型（MER）。方法：我们研究了肝切除术后一年内发生ER的HCC患者，并将其与术后5年无复发（RF）的患者进行比较。在测试集中，我们检测了全基因组甲基化谱，以识别ER与RF之间的差异。通过独立队列验证，使用实时定量甲基化特异性PCR（qMSP）确认了候选标志物。我们结合已识别的基因甲基化、临床信息和血清蛋白标志物构建了MER，并使用ROC分析和Cox回归评估其预测性能。结果：在ER与RF组之间，以及肝硬化与非肝硬化组之间，观察到显著的高甲基化和低甲基化特征。在非肝硬化ER患者中，观察到包括FGFR信号通路、PI3K网络和MAPK通路在内的显著异常甲基化通路。相反，肝硬化ER患者则显示出与Wnt/β-catenin信号通路、细胞粘附和迁移机制显著相关。通过qMSP分析，我们鉴定出与ER相关的基因，包括BDNF、FOXL2、LMO7、NCAM1、NEIS3、PLA2G7和LTB4R。MER显示出对ER的强大预测能力，AUC值为0.855，优于当前指标如AFP、肿瘤大小和BCLC分期。组合不同预测因子可提高AUC值。重要的是，纳入MER后获得了最高的AUC值0.952，突显了MER对预测准确性的显著贡献。结论：本研究发现了异常DNA甲基化在早期复发HCC中的参与。MER在识别ER风险患者方面优于临床病理学预测因子，并实现了强大的预测能力。
肿瘤(癌症)患者之家