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<p>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%; <i>P</i> &lt; 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 (<i>OTX1 and HIST1H3G</i>) 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 (<i>P</i> &lt; 0.001) while comparable with MBA-seq.&#xa0;HCCtect also demonstrated efficacy in early-stage HCC detection (sensitivity = 69.5%) and discrimination from chronic hepatitis B or liver cirrhosis (specificity = 93.0%). These findings establish ctDNA methylation as a superior approach over mutation analysis and highlight HCCtect as a promising non-invasive tool for HCC detection and high-risk population monitoring.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月29日

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  • Dezhen Guo,
  • Ao Huang,
  • Jianlong Sun,
  • Shiyu Zhang,
  • Jianwen Cheng,
  • Ruijingfang Jiang,
  • Yupeng Wang,
  • Huihao Chen,
  • Fengming Zhang,
  • Jiaxi Peng,
  • Jie Yuan,
  • Jiefei Wang,
  • Hongying Guo,
  • Zhong Chen,
  • Yongjun Chen,
  • Xuxiao Chen,
  • Shida Zhu,
  • Jia Fan,
  • Yuying Wang,
  • Xinrong Yang,
  • Jian Zhou

摘要

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 demonstrated efficacy in early-stage HCC detection (sensitivity = 69.5%) and discrimination from chronic hepatitis B or liver cirrhosis (specificity = 93.0%). These findings establish ctDNA methylation as a superior approach over mutation analysis and highlight HCCtect as a promising non-invasive tool for HCC detection and high-risk population monitoring.