Kim Da-Won, Park Jin Hyun, Hong Suk Kyun, Jung Min-Hyeok, Pyeon Ji-One, Lee Jin-Young, Suh Kyung-Suk, Yi Nam-Joon, Choi YoungRok, Lee Kwang-Woong, Kim Young-Joon
Interdisciplinary Program of Integrated OMICS for Biomedical Science, Yonsei University, Seoul, Korea.
R&D center, LepiDyne Inc, Seoul, Korea.
Clin Mol Hepatol. 2025 Apr;31(2):563-576. doi: 10.3350/cmh.2024.0899. Epub 2025 Jan 13.
BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) exhibits high de novo recurrence rates post-resection. Current post-surgery recurrence prediction methods are limited, emphasizing the need for reliable biomarkers to assess recurrence risk. We aimed to develop methylation-based markers for classifying HCC patients and predicting their risk of de novo recurrence post-surgery.
In this retrospective cohort study, we analyzed data from HCC patients who underwent surgical resection in Korea, excluding those with recurrence within one year post-surgery. Using the Infinium Methylation EPIC array on 140 samples in the discovery cohort, we classified patients into low- and high-risk groups based on methylation profiles. Distinctive markers were identified through random forest analysis. These markers were validated in the cancer genome atlas (n=217), Validation cohort 1 (n=63) and experimental Validation using a methylation-sensitive high-resolution melting (MS-HRM) assay in Validation cohort 1 and Validation cohort 2 (n=63).
The low-risk recurrence group (methylation group 1; MG1) showed a methylation average of 0.73 (95% confidence interval [CI] 0.69-0.77) with a 23.5% recurrence rate, while the high-risk group (MG2) had an average of 0.17 (95% CI 0.14-0.20) with a 44.1% recurrence rate (P<0.03). Validation confirmed the applicability of methylation markers across diverse populations, showing high accuracy in predicting the probability of HCC recurrence risk (area under the curve 96.8%). The MS-HRM assay confirmed its effectiveness in predicting de novo recurrence with 95.5% sensitivity, 89.7% specificity, and 92.2% accuracy.
Methylation markers effectively classified HCC patients by de novo recurrence risk, enhancing prediction accuracy and potentially offering personalized management strategies.
背景/目的:肝细胞癌(HCC)切除术后具有较高的新发复发率。目前的术后复发预测方法有限,这凸显了需要可靠的生物标志物来评估复发风险。我们旨在开发基于甲基化的标志物,用于对HCC患者进行分类,并预测其术后新发复发风险。
在这项回顾性队列研究中,我们分析了韩国接受手术切除的HCC患者的数据,排除术后一年内复发的患者。在发现队列的140个样本上使用Infinium甲基化EPIC芯片,我们根据甲基化谱将患者分为低风险和高风险组。通过随机森林分析确定独特的标志物。这些标志物在癌症基因组图谱(n = 217)、验证队列1(n = 63)中进行了验证,并在验证队列1和验证队列2(n = 63)中使用甲基化敏感的高分辨率熔解(MS-HRM)分析进行了实验验证。
低风险复发组(甲基化组1;MG1)的甲基化平均值为0.73(95%置信区间[CI] 0.69 - 0.77),复发率为23.5%,而高风险组(MG2)的平均值为0.17(95% CI 0.14 - 0.20),复发率为44.1%(P < 0.03)。验证证实了甲基化标志物在不同人群中的适用性,在预测HCC复发风险概率方面具有较高的准确性(曲线下面积为96.8%)。MS-HRM分析证实其在预测新发复发方面有效,敏感性为95.5%,特异性为89.7%,准确性为92.2%。
甲基化标志物可根据新发复发风险有效地对HCC患者进行分类,提高预测准确性,并可能提供个性化的管理策略。