Identification of a G-quadruplex-forming cell-free DNA fragment as a biomarker for the precise diagnosis of hepatocellular carcinoma
- 1School of Biomedical Engineering & Suzhou Institute for Advanced Research, University of Science and Technology of China Suzhou 215123 China
- 2New Cornerstone Science Laboratory, Department of Chemistry, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University Beijing 100084 China
- 3Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China Hefei China
Abstract
Early detection of hepatocellular carcinoma (HCC) remains challenging, as the currently recommended surveillance strategy based on ultrasound combined with alpha-fetoprotein (AFP) is limited by suboptimal sensitivity and accessibility. Cell-free DNA (cfDNA) provides a minimally invasive avenue for cancer detection. However, most existing cfDNA-based approaches either perform unreliably in low-input samples or require analytically complex workflows. Here, we systematically profiled serum cfDNA from individuals with HCC and without HCC and identified a high-abundance tumor-associated single cfDNA fragment at the FAM230F genomic region. Integrative analysis of liver assay for transposase-accessible chromatin with sequencing (ATAC-seq) data revealed consistent tumor-specific chromatin accessibility at this locus, suggesting a tumor-derived origin. Structural characterization further demonstrated enrichment of G-quadruplex (G4) features within the target sequence, which may increase resistance to serum nuclease degradation and promote its preferential retention in circulation. Based on these properties, we established a qPCR-based detection workflow with clinical accessibility. In a validation cohort independent of the discovery cohort, a ΔCt cutoff of 2 was selected by maximizing the Youden index within the same cohort. The assay showed a sensitivity of 94.5% and a specificity of 90.5% for distinguishing HCC from non-HCC. Collectively, our study identifies FAM230F as a structurally stable tumor-associated cfDNA fragment and establishes a simple and scalable qPCR-based assay for HCC detection, providing a practical framework for translating cfDNA fragment analysis into clinical biomarkers.
Related
- Missed Diagnosis in Alcohol‐Related Hepatocellular Carcinoma: A Call for Alcohol Consumption and Liver Disease Early Detection
- Adherencia a la vigilancia del carcinoma hepatocelular y su asociación con el estadio tumoral al diagnóstico: experiencia de un hospital universitario Adherence to Hepatocellular Carcinoma Surveillance and Its Association with Tumor Stage at Diagnosis: Experience at a University Hospital
- Artificial Intelligence‐Optimized Image Biomarker Identification for Sinonasal Inverted Papilloma Diagnosis Using Image‐Enhanced Versus White‐Light Endoscopy
- Identification of hepatitis B virus-associated membrane proteins as prognostic biomarkers for hepatocellular carcinoma based on retrospective analysis of integrated membrane proteomics
- BRIX1 Promotes Hepatocellular Carcinoma Progression via the MAPK/ERK Pathway and Serves as a Prognostic Biomarker
BibTeX
@article{sun2026identification,
title = {{Identification of a G-quadruplex-forming cell-free DNA fragment as a biomarker for the precise diagnosis of hepatocellular carcinoma}},
author = {Jianzhe Sun and Xucong Teng and Weizhi Zhang and Yicong Dai and Lianxin Liu and Jinghong Li},
journal = {Chemical Science},
year = {2026},
month = sep,
doi = {10.1039/d6sc04173f},
url = {https://doi.org/10.1039/d6sc04173f},
note = {CC BY-NC 3.0},
}
RIS
TY - JOUR
TI - Identification of a G-quadruplex-forming cell-free DNA fragment as a biomarker for the precise diagnosis of hepatocellular carcinoma
AU - Jianzhe Sun
AU - Xucong Teng
AU - Weizhi Zhang
AU - Yicong Dai
AU - Lianxin Liu
AU - Jinghong Li
PY - 2026
DA - 2026/09/03
JO - Chemical Science
DO - 10.1039/d6sc04173f
UR - https://doi.org/10.1039/d6sc04173f
AB - Early detection of hepatocellular carcinoma (HCC) remains challenging, as the currently recommended surveillance strategy based on ultrasound combined with alpha-fetoprotein (AFP) is limited by suboptimal sensitivity and accessibility. Cell-free DNA (cfDNA) provides a minimally invasive avenue for cancer detection. However, most existing cfDNA-based approaches either perform unreliably in low-input samples or require analytically complex workflows. Here, we systematically profiled serum cfDNA from individuals with HCC and without HCC and identified a high-abundance tumor-associated single cfDNA fragment at the FAM230F genomic region. Integrative analysis of liver assay for transposase-accessible chromatin with sequencing (ATAC-seq) data revealed consistent tumor-specific chromatin accessibility at this locus, suggesting a tumor-derived origin. Structural characterization further demonstrated enrichment of G-quadruplex (G4) features within the target sequence, which may increase resistance to serum nuclease degradation and promote its preferential retention in circulation. Based on these properties, we established a qPCR-based detection workflow with clinical accessibility. In a validation cohort independent of the discovery cohort, a ΔCt cutoff of 2 was selected by maximizing the Youden index within the same cohort. The assay showed a sensitivity of 94.5% and a specificity of 90.5% for distinguishing HCC from non-HCC. Collectively, our study identifies FAM230F as a structurally stable tumor-associated cfDNA fragment and establishes a simple and scalable qPCR-based assay for HCC detection, providing a practical framework for translating cfDNA fragment analysis into clinical biomarkers.
SN - 2041-6520
SN - 2041-6539
ER -