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In the present study, we established an epigenetic liquid biopsy assay for the preoperative diagnosis of LNM in T1 GC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A comprehensive biomarker discovery was performed by analyzing genome\u2010wide DNA methylation profiling. We obtained 277 clinical specimens, including 177 surgical tissues and 100 pre\u2010operative plasmas. DNA methylation biomarkers were trained and validated using quantitative methylation\u2010specific polymerase chain reaction (qMSP) assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified six novel differentially methylated regions, including at least two differentially methylated CpG probes (|Delta\u2010beta| &gt;\u00a00.12 and\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&lt;\u00a00.05) within 100 bp, through genome\u2010wide biomarker discovery. A DNA methylation panel was generated using qMSP assays in clinical tissue specimens, with an area under the curve (AUC) of 0.80. This panel was validated in an independent clinical cohort, and a combined model, which integrated the DNA methylation model with preoperative computed tomography \u2010based findings, was established through multivariate logistic regression analyses (AUC: 0.84). Finally, we translated this model into a liquid biopsy, and this cell\u2010free DNA (cfDNA) methylation model exhibited robust performance for LNM identification in T1 GC (AUC: 0.86) and allowed 44% of patients to avoid unnecessary invasive operations, without missing any LNM\u2010positive patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We have successfully developed a cfDNA methylation signature\u2010based liquid biopsy diagnostic assay that allows for robust and less\u2010invasive LNM detection in patients with T1 GC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ueg2.70132","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T16:24:33Z","timestamp":1760718273000},"page":"2023-2033","source":"Crossref","is-referenced-by-count":2,"title":["Cell\u2010Free DNA Methylation\u2010Based Liquid Biopsy Assay to Identify Lymph Node Metastasis in T1 Gastric Cancer"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-6964-2726","authenticated-orcid":false,"given":"Keisuke","family":"Okuno","sequence":"first","affiliation":[{"name":"Department of Gastrointestinal Surgery Institute of Science Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adwait","family":"Joshi","sequence":"additional","affiliation":[{"name":"Imperial College School of Medicine  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuichi","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Division of Cellular Signaling National Cancer Center Research Institute  Tokyo Japan"},{"name":"Department of Hepatobiliary and Pancreatic Surgery Institute of Science Tokyo  Tokyo 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