Cell-free DNA in hepatocellular carcinoma: Biology to treatment response

Table 1 Diagnostic performance of cell-free DNA-based biomarkers for hepatocellular carcinoma detection

Ref.	Patients (HCC cohort)	cfDNA characteristics	Sensitivity	Specificity	AUROC
Xu et al[6], 2017	1098 (training + validation)	HCC bisulphite methylation marker	86%	94%	0.97 (0.96-0.98)
Cai et al[7], 2019	1204 tests	5-hMC signatures	79%	91%	0.92 (0.88-0.92)
Cai et al[8], 2021	135 (training + tests)	5-hMC, AFP and PIVKA2	79%	91%	0.92 (0.88-0.92)
Chen et al[9], 2021	350 (training + validation)	HIFI score = 4 cfDNA genomic features	96%	95%	0.995 (0.99-1.000)
Luo et al[10], 2022	187 (training + validation)	cfDNA methylation	86%	98%	0.98 (0.97-0.99)
Pös et al[11], 2020	159 (training)	cfDNA fragmentomic profiles	97%	99%	0.995
Kim et al[22], 2023	313 tests	Methylation markers of RNF135 and LDHB	57%	94%	0.80 (0.76-0.83)
Guo et al[41], 2024	498 (training + validation)	DMRs HepaAiQ: 20 best DMRs	86%	92%	0.94 (0.93-0.96)
Chen et al[44], 2024	510 (stage1)	PreCar score = 5 cfDNA genomic features	94%	95%	NA

Summarizes index tests, cohort structures (training, validation, and test where applicable), and corresponding sensitivity, specificity, and area under the receiver operating characteristic curve as reported by the original studies, enabling side-by-side appraisal of cell-free DNA methylation, hydroxymethylation, fragmentomics, and integrated multi-feature models for hepatocellular carcinoma detection in at-risk populations and mixed clinical cohorts. HCC: Hepatocellular carcinoma; cfDNA: Cell-free DNA; AUROC: Area under the receiver operating characteristic curve; 5-hmC: 5-hydroxymethylcytosine motif; AFP: Alpha-fetoprotein; PIVKA2: Protein induced by vitamin K absence or antagonist-II; HIFI: Integrated model of 5-hydroxymethylcytosine motif/fragmentation/nucleosome footprint; RNF135: Ring finger protein 135; LDHB: Lactate dehydrogenase B; DMR: Differentially methylated region; HepaAiQ: Hepatic artificial intelligence quantitative; NA: Not available.