{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:38:59Z","timestamp":1785425939291,"version":"3.56.0"},"reference-count":27,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T00:00:00Z","timestamp":1781913600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Institute of Health Carlos III","doi-asserted-by":"publisher","award":["(FI22\/00273)"],"award-info":[{"award-number":["(FI22\/00273)"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"award":["(FI22\/00273)"],"award-info":[{"award-number":["(FI22\/00273)"]}],"id":[{"id":"https:\/\/ror.org\/00ca2c886","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 &lt; 0.0001) and longer fragment lengths (p &lt; 0.05) compared to LC patients. The CMAC model demonstrated superior diagnostic performance (AUROC = 0.946) compared to AFP alone (AUROC = 0.777, p &lt; 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.<\/jats:p>","DOI":"10.3390\/ijms27125590","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T03:09:17Z","timestamp":1782270557000},"page":"5590","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Circulating Cell-Free DNA Analysis for Diagnostic and Prognostic Assessment of Hepatocellular Carcinoma in Cirrhosis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4902-214X","authenticated-orcid":false,"given":"In\u00e9s","family":"Aznar-Peralta","sequence":"first","affiliation":[{"name":"GENYO, Centre for Genomics and Oncological Research, Pfizer\/University of Granada\/Andalusian Regional Government, 18016 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amparo","family":"Roa-Colomo","sequence":"additional","affiliation":[{"name":"Digestive System Unit, Costa del Sol University Hospital, 29603 Marbella, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9106-2028","authenticated-orcid":false,"given":"Javier","family":"L\u00f3pez Hidalgo","sequence":"additional","affiliation":[{"name":"Department of Pathology, San Cecilio Clinical University Hospital\u2014Instituto de Investigaci\u00f3n Biosanitaria ibs GRANADA, 18012 Granada, Spain"},{"name":"Department of Pathology, Virgen de las Nieves University Hospital\u2014Instituto de Investigaci\u00f3n Biosanitaria ibs GRANADA, 18012 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2039-5188","authenticated-orcid":false,"given":"Cristobal","family":"Fresno","sequence":"additional","affiliation":[{"name":"Research Support Network, Scientific Research Coordination, National Autonomous University of Mexico, Mexico City 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3309-7801","authenticated-orcid":false,"given":"Valeria","family":"Denninghoff","sequence":"additional","affiliation":[{"name":"GENYO, Centre for Genomics and Oncological Research, Pfizer\/University of Granada\/Andalusian Regional Government, 18016 Granada, Spain"},{"name":"Department of Pathology, San Cecilio Clinical University Hospital\u2014Instituto de Investigaci\u00f3n Biosanitaria ibs GRANADA, 18012 Granada, Spain"},{"name":"Molecular-Clinical Laboratory, University of Buenos Aires (UBA)\u2014National Council for Scientific and Technical Research (CONICET), Buenos Aires C1053, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0298-9054","authenticated-orcid":false,"given":"Mar\u00eda","family":"Jos\u00e9 Serrano","sequence":"additional","affiliation":[{"name":"GENYO, Centre for Genomics and Oncological Research, Pfizer\/University of Granada\/Andalusian Regional Government, 18016 Granada, Spain"},{"name":"Department of Pathology, San Cecilio Clinical University Hospital\u2014Instituto de Investigaci\u00f3n Biosanitaria ibs GRANADA, 18012 Granada, Spain"},{"name":"Department of Pathology, Virgen de las Nieves University Hospital\u2014Instituto de Investigaci\u00f3n Biosanitaria ibs GRANADA, 18012 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,20]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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