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Although endoscopic screening and intervention can significantly reduce mortality associated with ESCC, they have certain shortcomings. We aimed to develop three predictive models: the motif, eight-protein, and combined motif-protein models to identify ESCC and its precancerous lesions.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Plasma samples were collected for cfDNA sequencing, and nine commonly used clinical protein biomarkers related to the digestive system were measured. Using a total cohort of 199 patients with ESCC, 91 patients with esophageal squamous precancerous lesions (ESPL), and 201 controls, we developed an integrative model based on selected multi-omics biomarkers.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>The motif-protein model, integrating 20 principal components of cfDNA terminal motifs with six protein features, outperformed both the motif model and the eight-protein model in distinguishing patients with ESCC and ESPL (area under the curve\u2009=\u20090\u00b790). It achieved an overall sensitivity of 88\u00b75% and a specificity of 75\u00b74%. Notably, it successfully identified 90\u00b79% of high-grade intraepithelial neoplasia cases, 86\u00b78% of stage I ESCC cases, and 87\u00b78% of HGIN or T1aN0 stage ESCC (subset of Stage I) cases who were eligible for endoscopic treatment, highlighting its potential as an effective tool for early diagnosis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>The motif-protein model may serve as an effective tool for the early diagnosis of esophageal lesions. Our findings underscore the clinical potential of the multi-omics liquid biopsy test as a non-invasive method for detecting early esophageal lesions.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s40364-025-00840-9","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T13:19:51Z","timestamp":1760447991000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Development and validation of predictive models combining cell-Free DNA motifs and protein biomarkers for early detection of esophageal squamous cell carcinoma and precancerous lesion"],"prefix":"10.1186","volume":"13","author":[{"given":"Liu","family":"Ma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lizhou","family":"Dou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueming","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xudong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoi-loi","family":"Ng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangtao","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumeng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengqi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Ke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guiqi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,14]]},"reference":[{"issue":"1","key":"840_CR1","first-page":"47","volume":"4","author":"B Han","year":"2024","unstructured":"Han B, Zheng R, Zeng H, Wang S, Sun K, Chen R, Li L, Wei W, He J. 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