Introduction Patients with hepatitis virus-related hepatocellular carcinoma (viral HCC) are decreasing as hepatitis control improves, but those with non-viral-related HCC (non-viral HCC) are increasing in Japan. No established surveillance system exists for patients with non-viral HCC, so they are often diagnosed at an advanced stage. To address this, we performed this study. Methods We collected serum samples from 516 participants (154 healthy subjects, 93 chronic liver disease [CLD] patients without HCC, and 269 HCC patients). Participants were divided into a control group comprising healthy subjects and patients with CLD and an HCC group. We evaluated serum methylated HOXA1 (m-HOXA1) copy numbers using modified combined restriction digital PCR (CORD) assay (1-step CORD assay). We assessed diagnostic performance of m-HOXA1 compared to HCC tumor markers alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) and created a novel index to improve HCC prediction. Results Serum m-HOXA1 level was significantly higher in each HCC stage group versus the control group. Its sensitivity was 69.1% and specificity was 78.5% for diagnosing HCC. The area under the curve (AUC) of m-HOXA1 was superior to that of AFP and equal to that of DCP. Multivariate logistic regression analysis revealed independent contributions of m-HOXA1, DCP, and AFP, in that order of strength, to diagnose HCC after adjustment for age and sex. We designated the predictive probability of HCC based on the regression model as the ASDAm-H1 (Age, Sex, DCP, AFP, and m-HOXA1) index. Its diagnostic accuracy was 0.96 by AUC with a sensitivity of 86.2% and specificity of 93.9%. Sensitivity was identical for viral and non-viral HCCs. When limited to early-stage HCC, sensitivity of the ASDAm-H1 index was 76.3%. Conclusions We showed distinguished performance of the ASDAm-H1 index to detect viral and non-viral HCC, even at an early stage. This index might have potential as a non-viral HCC surveillance system.

中文翻译：

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甲基化 HOXA1 与肿瘤标志物的联合检测显示对检测早期肝细胞癌具有很高的敏感性。


简介 随着肝炎控制的改善，肝炎病毒相关肝细胞癌 （病毒性肝细胞癌） 患者正在减少，但非病毒相关肝细胞癌 （非病毒性 HCC） 患者在日本正在增加。对于非病毒性 HCC 患者，没有建立的监测系统，因此他们通常在晚期被诊断出来。为了解决这个问题，我们进行了这项研究。方法 我们收集了 516 名参与者 （154 名健康受试者、93 名无 HCC 的慢性肝病 [CLD] 患者和 269 名 HCC 患者）的血清样本。参与者被分为对照组，包括健康受试者和 CLD 患者和 HCC 组。我们使用改良的联合限制性数字 PCR （CORD） 测定 （1 步 CORD 测定） 评估血清甲基化 HOXA1 （m-HOXA1） 拷贝数。我们评估了 m-HOXA1 与 HCC 肿瘤标志物甲胎蛋白 （AFP） 和 des-γ-羧基凝血酶原 （DCP） 相比的诊断性能，并创建了一个新指数来改善 HCC 预测。结果 各 HCC 分期组血清 m-HOXA1 水平显著高于对照组。其诊断 HCC 的敏感性为 69.1%，特异性为 78.5%。m-HOXA1 的曲线下面积 （AUC） 优于 AFP，与 DCP 相当。多因素 logistic 回归分析显示，在调整年龄和性别后，m-HOXA1 、 DCP 和 AFP 对诊断 HCC 的独立贡献（按强度顺序排列）。我们将基于回归模型的 HCC 预测概率指定为 ASDAm-H1 （年龄、性别、DCP、AFP 和 m-HOXA1） 指数。AUC 诊断准确率为 0.96，灵敏度为 86.2%，特异性为 93.9%。病毒和非病毒 HCC 的敏感性相同。当局限于早期 HCC 时，ASDAm-H1 指数的敏感性为 76.3%。 结论 我们展示了 ASDAm-H1 指数在检测病毒和非病毒 HCC 方面的出色表现，即使在早期阶段也是如此。该指数可能具有作为非病毒性 HCC 监测系统的潜力。