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This study aims to investigate the implications of 5hmC in the progression from gastric premalignant lesions to gastric adenocarcinoma (GAC).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To our knowledge, we conducted the largest and longest longitudinal study of a Chinese population with gastric precursor lesions, involving 29,176 patients with gastritis who underwent gastroscopy and biopsy between 2001 and 2015, with follow\u2010up until 1 August, 2022. The median follow\u2010up time was 12.2 years, and the overall GAC incidence rate was 0.82%. Genome\u2010wide mapping of 5hmC in gastric premalignant lesions from a subset of individuals was performed using the 5hmC\u2010Seal assay, including 21 samples that progressed to GAC during follow\u2010up and 48 non\u2010progressed age\u2010 and sex\u2010matched controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified 213 differentially modified gene bodies, primarily concentrated in pathways related to cell division, cell cycle, energy metabolism, inflammation and tumourigenesis. An exploratory study was conducted to summarize a 5hmC\u2010based epigenetic model for predicting cancer progression using multivariable logistic regression and machine learning. The nine\u2010gene model showed an area under the curve of 87.5% (95% confidence interval: 72%\u2013100%) in the validation samples (one of three), which were set aside before model training.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study is the first to explore the 5hmC molecular landscape in gastric premalignant lesions, suggesting relevant pathways implicated in their evolution to GAC as well as the feasibility of exploiting genome\u2010wide 5hmC mapping in assessing the risk of future cancer progression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>A largest longitudinal follow\u2010up study of gastric precursor lesions in Chinese patients.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Revealing novel 5hmC molecular landscape linked to gastric premalignant lesions.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The feasibility of an innovative 5hmC\u2010based predictive model for assessing gastric cancer progression risk.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.70114","type":"journal-article","created":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T12:56:05Z","timestamp":1733230565000},"source":"Crossref","is-referenced-by-count":6,"title":["Elucidating epigenetic landscape of gastric premalignant lesions through genome\u2010wide mapping of 5\u2010hydroxymethylcytosines: A 12\u2010year median follow\u2010up study"],"prefix":"10.1002","volume":"14","author":[{"given":"Zhongguang","family":"Luo","sequence":"first","affiliation":[{"name":"Department of Digestive Diseases Huashan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenshuai","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Digestive Diseases Huashan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3916-7348","authenticated-orcid":false,"given":"Wanwei","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Digestive Diseases Huashan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixiang","family":"Shi","sequence":"additional","affiliation":[{"name":"Bionova (Shanghai) Medical Technology Co., Ltd.  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