Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2025 Mar 20;17(6):1042.
doi: 10.3390/cancers17061042.

The Current Role of Circulating Cell-Free DNA in the Management of Hepatocellular Carcinoma

Alkistis Papatheodoridi  1 , Vasileios Lekakis  2 , Antonios Chatzigeorgiou  3 , George Papatheodoridis  2
Affiliations
Review

The Current Role of Circulating Cell-Free DNA in the Management of Hepatocellular Carcinoma

Alkistis Papatheodoridi et al. Cancers (Basel). .

Abstract

Circulating cell-free DNA (cfDNA) has emerged as a compelling candidate of liquid biopsy markers for the diagnosis and prognosis of several cancers. We systematically reviewed data on the role of cfDNA markers in the diagnosis, prognosis and treatment of hepatocellular carcinoma (HCC). Early studies suggested that levels of circulating cfDNA, mitochondrial DNA and cfDNA integrity are higher in patients with HCC than chronic liver diseases. In subsequent studies, methylation changes in circulating tumor DNA (ctDNA) as well as cfDNA fragmentation patterns and circulating nucleosomes were found to offer high sensitivity (>60%) and excellent specificity (>90%) for HCC diagnosis. The predictive role of cfDNA markers and ctDNA has been assessed in a few studies including untreated patients with HCC providing promising results for prediction of survival. However, port-hepatectomy detection of cfDNA/ctDNA markers or copy number variation indicators of cfDNA seem to reflect minimum residual disease and thus a high risk for HCC recurrence. The same markers can be useful for prediction after transarterial chemoembolization, radiofrequency ablation, radiotherapy and even systemic therapies. In conclusion, cfDNA markers can be useful in HCC surveillance, improving early diagnosis rates, as well as for monitoring treatment effectiveness and minimal residual disease post-treatment.

Keywords: cell-free DNA; hepatocellular carcinoma; methylation; tumor DNA.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Progression of cell-free DNA (cfDNA) research in hepatocellular carcinoma (HCC): key milestones and future perspectives.
Figure 2
Figure 2
Cell-free DNA research in hepatocellular carcinoma over the years.
Figure 3
Figure 3
Cell-free DNA (cfDNA) species used for diagnosis of hepatocellular carcinoma. Created in BioRender, Papatheodoridi A (2025).
See this image and copyright information in PMC

References

    1. Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018;68:394–424. - PubMed
    1. McGlynn K.A., Petrick J.L., El-Serag H.B. Epidemiology of Hepatocellular Carcinoma. Hepatology. 2021;73((Suppl. S1)):4–13. doi: 10.1002/hep.31288. - DOI - PMC - PubMed
    1. Villanueva A. Hepatocellular Carcinoma. N. Engl. J. Med. 2019;380:1450–1462. doi: 10.1056/NEJMra1713263. - DOI - PubMed
    1. EASL EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J. Hepatol. 2018;69:182–236. doi: 10.1016/j.jhep.2018.03.019. - DOI - PubMed
    1. Llovet J.M., Kelley R., Villanueva A., Singal A., Pikarsky E., Roayaie S., Lencioni R., Koike K., Zucman-Rossi J., Finn R.S. Hepatocellular carcinoma. Nat. Rev. Dis. Primers. 2021;7:6. doi: 10.1038/s41572-020-00240-3. - DOI - PubMed

LinkOut - more resources