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Volume 27
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Article

Circulating Cell-Free DNA Analysis for Diagnostic and Prognostic Assessment of Hepatocellular Carcinoma in Cirrhosis

by
Inés Aznar-Peralta
1,
Amparo Roa-Colomo
2,
Javier López Hidalgo
3,4,
Cristobal Fresno
5,
Valeria Denninghoff
1,3,6,* and
María José Serrano
1,3,4,*
1
GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, 18016 Granada, Spain
2
Digestive System Unit, Costa del Sol University Hospital, 29603 Marbella, Spain
3
Department of Pathology, San Cecilio Clinical University Hospital—Instituto de Investigación Biosanitaria ibs GRANADA, 18012 Granada, Spain
4
Department of Pathology, Virgen de las Nieves University Hospital—Instituto de Investigación Biosanitaria ibs GRANADA, 18012 Granada, Spain
5
Research Support Network, Scientific Research Coordination, National Autonomous University of Mexico, Mexico City 04510, Mexico
6
Molecular-Clinical Laboratory, University of Buenos Aires (UBA)—National Council for Scientific and Technical Research (CONICET), Buenos Aires C1053, Argentina
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2026, 27(12), 5590; https://doi.org/10.3390/ijms27125590 (registering DOI)
Submission received: 16 May 2026 / Revised: 15 June 2026 / Accepted: 15 June 2026 / Published: 20 June 2026
(This article belongs to the Special Issue Biomarkers in Oncology)
Review Reports Versions Notes

Abstract

Early detection of hepatocellular carcinoma (HCC) is crucial for curative treatment, yet current screening strategies for high-risk liver cirrhosis (LC) patients lack sufficient sensitivity. This study evaluates plasma cell-free DNA(cfDNA) concentration and fragmentomics as biomarkers to improve HCC diagnosis and prognosis. Plasma samples from 39 HCC and 46 LC patients were analyzed for cfDNA concentration and fragment patterns. A multivariate logistic regression model (CMAC), integrating cfDNA concentration, mononucleosome proportion (%MN), alpha-fetoprotein (AFP), and c-reactive protein (CRP), was developed and validated using Leave-One-Out Cross-Validation and bootstrapping. HCC patients exhibited significantly higher cfDNA concentrations (p < 0.0001) and longer fragment lengths (p < 0.05) compared to LC patients. The CMAC model demonstrated superior diagnostic performance (AUROC = 0.946) compared to AFP alone (AUROC = 0.777, p < 0.001). Notably, in early-stage HCC, the CMAC model remained highly accurate (AUROC = 0.941), whereas AFP failed to reach statistical significance. Higher CMAC scores were significantly associated with advanced BCLC stages (p = 0.009), lymphovascular invasion (p = 0.0063) and reduced overall survival (p = 0.0037). Integration of cfDNA analysis with established clinical markers in the CMAC model shows promise as a complementary tool for the early detection of HCC in LC patients. Validation in larger, multicenter cohorts will be necessary to confirm these findings and their clinical applicability.
Keywords: circulating free DNA; fragmentomics; cancer biomarker; hepatocarcinoma; cirrhosis; liquid biopsy; prognostic and predictive markers circulating free DNA; fragmentomics; cancer biomarker; hepatocarcinoma; cirrhosis; liquid biopsy; prognostic and predictive markers

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MDPI and ACS Style

Aznar-Peralta, I.; Roa-Colomo, A.; López Hidalgo, J.; Fresno, C.; Denninghoff, V.; José Serrano, M. Circulating Cell-Free DNA Analysis for Diagnostic and Prognostic Assessment of Hepatocellular Carcinoma in Cirrhosis. Int. J. Mol. Sci. 2026, 27, 5590. https://doi.org/10.3390/ijms27125590

AMA Style

Aznar-Peralta I, Roa-Colomo A, López Hidalgo J, Fresno C, Denninghoff V, José Serrano M. Circulating Cell-Free DNA Analysis for Diagnostic and Prognostic Assessment of Hepatocellular Carcinoma in Cirrhosis. International Journal of Molecular Sciences. 2026; 27(12):5590. https://doi.org/10.3390/ijms27125590

Chicago/Turabian Style

Aznar-Peralta, Inés, Amparo Roa-Colomo, Javier López Hidalgo, Cristobal Fresno, Valeria Denninghoff, and María José Serrano. 2026. "Circulating Cell-Free DNA Analysis for Diagnostic and Prognostic Assessment of Hepatocellular Carcinoma in Cirrhosis" International Journal of Molecular Sciences 27, no. 12: 5590. https://doi.org/10.3390/ijms27125590

APA Style

Aznar-Peralta, I., Roa-Colomo, A., López Hidalgo, J., Fresno, C., Denninghoff, V., & José Serrano, M. (2026). Circulating Cell-Free DNA Analysis for Diagnostic and Prognostic Assessment of Hepatocellular Carcinoma in Cirrhosis. International Journal of Molecular Sciences, 27(12), 5590. https://doi.org/10.3390/ijms27125590

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