{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T18:28:39Z","timestamp":1791224919759,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100018538","name":"National Ten Thousand Talent Program","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100018538","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and aims<\/jats:title>\n                    <jats:p>Existing imaging and serum\u2010marker assays miss many early liver cancers, especially in high\u2010risk chronic liver disease carriers. We aimed to create a highly accurate, non\u2010invasive, methylation\u2010based liquid biopsy for early detection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We used a comprehensive, multi\u2010platform, multi\u2010cohort strategy for marker discovery, starting with methylation profiling of hepatocellular carcinoma samples from TCGA and in\u2010house cohorts. From 30 initial candidates, nine highly liver\u2010specific methylation markers were shortlisted, and three optimal cfDNA markers (RNF135, CHFR, PAX5) were selected to develop a robust diagnostic model, tuned in a training set (\n                      <jats:italic>N<\/jats:italic>\n                      \u00a0=\u00a0280) and locked in an internal testing set (\n                      <jats:italic>N<\/jats:italic>\n                      \u00a0=\u00a0124). The model was then validated in a prospective, large\u2010scale trial conducted at four geographically distinct Chinese centres.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The clinical trial included 1097 participants from two groups, (i) a diagnosing group (\n                      <jats:italic>N<\/jats:italic>\n                      \u00a0=\u00a0646) that prospectively enrolled individuals without prior diagnostic results and represented a real\u2010world high\u2010risk population, and (ii) a diagnosed group recruited after pathology confirmation. Overall, the model achieved 94.43% (95% confidence interval, 92.12\u201396.09%) sensitivity and 95.16% (92.78\u201396.78%) specificity for liver cancer, with stage\u2010I sensitivity of 93.10% (89.78\u201395.40%). Within the diagnosing group, overall sensitivity was 93.99% (91.28\u201395.90%), and for the 267 stage\u2010I cases, it reached 92.88% (89.15\u201395.39%). As for specificity, it remained high across confounders: 92.78% (85.84\u201396.46%) in cirrhosis, 91.74% (85.46\u201395.45%) in other\u2010cancer interference samples. Besides, the model outperformed the traditional liver cancer biomarker AFP and showed changes in methylation signals before and after surgery, suggesting a possible role in perioperative monitoring. Each centre independently reported sensitivities and specificities exceeding 90%, demonstrating robust geographic performance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Using a systematic marker\u2010discovery pipeline and a multi\u2010centre prospective cohort, we developed a methylation\u2010based liquid biopsy that reliably detects early liver cancer in high\u2010risk populations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical trial number<\/jats:title>\n                    <jats:p>Chictr.org identifier: ChiCTR2400092883.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Three cfDNA methylation markers, RNF135, CHFR and PAX5, were identified for liver cancer liquid biopsy.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>A three\u2010marker diagnostic model based on qMSP was established for highly accurate non\u2010invasive detection of liver cancer.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The LC\u2010HMC model achieved 94.43% sensitivity and 95.16% specificity in the clinical trial.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The model detected stage\u2010I liver cancer with a sensitivity of 93.10%.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70687","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T08:31:48Z","timestamp":1779093108000},"source":"Crossref","is-referenced-by-count":2,"title":["A multi\u2010centre, prospective trial of a methylation\u2010based liquid biopsy for early detection of liver cancer in high\u2010risk populations"],"prefix":"10.1002","volume":"16","author":[{"given":"Ruohan","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary Surgery Xijing Hospital Air Force Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2716-9338","authenticated-orcid":false,"given":"Xinrong","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Liver Surgery &amp; Transplantation Liver Cancer Institute Zhongshan Hospital Fudan Universi ty and Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangming","family":"Li","sequence":"additional","affiliation":[{"name":"Department of General Surgery Center Beijing Youan Hospital Capital Medical University  Beijing China"},{"name":"Clinical Center for Liver Cancer Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinan","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Hepatic Surgery &amp; Liver Transplantation The Third Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3674-1447","authenticated-orcid":false,"given":"Jibing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Interventional Therapy I Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjun","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory State Key Laboratory of Molecular Oncology National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College, Chaoyang District  Beijing China"},{"name":"Department of Clinical Laboratory Shanxi Province Cancer Hospital Shanxi Hospital Chinese Academy of Medical Sciences  Taiyuan Shanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Research &amp; Development BioChain (Beijing) Science &amp; Technology, Inc.  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