Introduction: Alfa-fetoprotein (AFP), as the main serum tumor marker of hepatocellular carcinoma (HCC), is limited in terms of specificity and ability to predict outcomes. This study investigated the clinical utility of DNA methylation biomarkers to predict therapeutic responses and prognosis in intermediate-stage HCC. Methods: This study enrolled 72 patients with intermediate-stage HCC who underwent locoregional therapy (LRT) between 2020 and 2021. The immediate therapeutic response and disease status during a two-year follow-up were recorded. Analysis was performed on 10 selected DNA methylation biomarkers via pyrosequencing analysis of plasma collected before and after LRT. Results: Analysis was performed on 53 patients with complete responses and 19 patients with disease progression after LRT. The mean follow-up duration was 2.4 ± 0.6 years. A methylation prediction model for tumor response (MMTR) and a methylation prediction model for early progression (MMEP) were constructed. The area under the curve (AUC) for sensitivity and specificity of MMTR was 0.79 for complete response and 0.759 for overall survival. The corresponding AUCs for sensitivity and specificity of AFP and protein induced by vitamin K absence-II (PIVKA-II) were 0.717 and 0.708, respectively. Note that the MMTR index was the only significant predictor in multivariate analysis. The AUC for sensitivity and specificity of the MMEP in predicting early progression was 0.79. The corresponding AUCs for sensitivity and specificity of AFP and PIVKA-II were 0.758 and 0.714, respectively. Multivariate analysis revealed that platelet count, beyond up-to-7 criteria, and the MMEP index were strongly correlated with early tumor progression. Combining the indexes and serum markers further improved the predictive accuracy (AUC = 0.922). Multivariate analysis revealed the MMEP index was the only independent risk factor for overall survival. Discussion/Conclusions: This study indicates that these methylation markers could potentially outperform current serum markers in terms of accuracy and reliability in assessing treatment response and predicting outcomes. Combining methylation markers and serum markers further improved predictive accuracy, indicating that a multi-marker approach may be more effective in clinical practice. These findings suggest that DNA methylation biomarkers may be a useful tool for managing intermediate-stage HCC patients and guiding personalized treatment, particularly for those who are at high risk for close surveillance or adjuvant treatment after LRT.
引言：甲胎蛋白（AFP）作为肝细胞癌（HCC）的主要血清肿瘤标志物，在特异性及预后预测能力方面存在局限。本研究探讨了DNA甲基化生物标志物在预测中期HCC治疗反应及预后的临床应用价值。方法：本研究纳入2020年至2021年间接受局部区域治疗（LRT）的72例中期HCC患者，记录其即刻治疗反应及两年随访期间的疾病状态。通过焦磷酸测序技术对LRT前后采集的血浆样本中10个选定的DNA甲基化生物标志物进行分析。结果：对LRT后获得完全缓解的53例患者和疾病进展的19例患者进行分析，平均随访时间为2.4±0.6年。研究构建了肿瘤反应甲基化预测模型（MMTR）和早期进展甲基化预测模型（MMEP）。MMTR预测完全缓解的敏感度与特异度曲线下面积（AUC）为0.79，预测总生存期的AUC为0.759；而AFP和维生素K缺乏诱导蛋白-II（PIVKA-II）的对应AUC分别为0.717和0.708。值得注意的是，在多变量分析中MMTR指数是唯一具有显著意义的预测因子。MMEP预测早期进展的敏感度与特异度AUC为0.79；AFP和PIVKA-II的对应AUC分别为0.758和0.714。多变量分析显示血小板计数、超"up-to-7"标准及MMEP指数与早期肿瘤进展密切相关。联合指数与血清标志物可进一步提升预测准确性（AUC=0.922）。多变量分析表明MMEP指数是总生存期的唯一独立危险因素。讨论/结论：本研究表明这些甲基化标志物在评估治疗反应和预测预后方面，其准确性与可靠性可能优于现有血清标志物。甲基化标志物与血清标志物联合应用可进一步提高预测精度，提示多标志物联合策略在临床实践中可能更具效能。这些发现表明DNA甲基化生物标志物或可作为管理中期HCC患者、指导个体化治疗的有效工具，尤其适用于LRT后需密切监测或辅助治疗的高风险患者。
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