The genomic and epigenomic abnormalities of plasma cfDNA as liquid biopsy biomarkers to detect hepatocellular carcinoma: a multicenter cohort study

作者：De‐Zhen Guo, Ao Huang, Jianlong Sun, Shiyu Zhang, Jianwen Cheng, Ruijingfang Jiang, Yupeng Wang, Yupeng Wang, 陈慧豪, Fengming Zhang, Jiaxi Peng, Jie Yuan, Jiefei Wang, Hongying Guo, Yongjun Chen, Xuxiao Chen, Xuxiao Chen, Shida Zhu, Jia Fan, Xin-Rong Yang, Yuying Wang, Xin-Rong Yang, Jian Zhou · 发表于：Journal of Hematology & Oncology · 年份：2025 · DOI：10.1186/s13045-025-01747-6 · 被引用次数：11 · 研究领域：Cancer Genomics and Diagnostics、Hepatocellular Carcinoma Treatment and Prognosis、Epigenetics and DNA Methylation

Circulating tumor DNA (ctDNA) is a promising biomarker for early cancer detection; however, the optimal biomarker approach for early detection of hepatocellular carcinoma (HCC) remains unclear. Furthermore, current next-generation sequencing-based detection methods remain costly and complex, limiting their clinical utility for high-risk population screening. Hence, this study compared ctDNA mutation and methylation for HCC detection and aimed to develop a clinically accessible assay. A total of 1965 participants, including 629 HCC and 1336 control participants, were enrolled in five centers. Parallel ultra-deep targeted sequencing and targeted bisulfite sequencing revealed that a methylation-based ctDNA model significantly outperformed the mutation model in detecting HCC (sensitivity, 92.1% vs. 63.7%; P < 0.001), with no added benefit from combining both markers. We subsequently developed a multiplex PCR-based bisulfite amplicon sequencing assay (MBA-seq) using 25 selected methylation markers, achieving high diagnostic accuracy (AUC = 0.958, sensitivity = 86.7%, specificity = 90.1%) in the testing set. Further refinement through AUC-based selection yielded a two-marker panel (OTX1 and HIST1H3G) adapted into a quantitative methylation-specific PCR assay, designated HCCtect. This optimized model showed robust performance (AUC = 0.925, sensitivity = 78.4%, specificity = 93.0%), significantly surpassing alpha-fetoprotein (P < 0.001) while comparable with MBA-seq. HCCtect also dem...