{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T04:47:18Z","timestamp":1792039638369,"version":"4.4.0"},"reference-count":33,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Bladder cancer surveillance remains challenging because conventional methods do not fully capture the biological heterogeneity within histologically low-grade urothelial carcinoma (LGUC). We evaluated whether urinary DNA methylation profiling using Bladder EpiCheck\u2122 can identify clinically relevant LGUC subgroups in a retrospective single-center cohort of 134 patients with paired histopathology, urine cytology, and methylation results. Methylation positivity increased across negative histopathology, LGUC, and high-grade urothelial carcinoma (HGUC) (18.4%, 51.4%, and 91.5%, respectively). Within LGUC, 19 of 37 tumors (51.4%) were methylation-positive. Their EpiScores overlapped those of HGUC, whereas methylation-negative LGUCs exhibited scores similar to negative histopathology. Gaussian mixture modeling independently supported a bimodal distribution. Methylation-positive LGUCs demonstrated a higher Ki67 labeling index, more frequent MTAP loss (33.3% vs. 11.8%), and more recurrences, including recurrence as HGUC, than methylation-negative LGUCs. Conventional nuclear morphometry did not distinguish between the two LGUC subgroups. These exploratory findings suggest that urinary DNA methylation may identify a biologically distinct subset of histologically low-grade tumors with selected high-grade-associated features. Prospective external validation is required before methylation status can inform surveillance or treatment decisions.<\/jats:p>","DOI":"10.3390\/ijms27198934","type":"journal-article","created":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T01:40:17Z","timestamp":1791596417000},"page":"8934","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Urinary DNA Methylation Profiling Identifies a Biologically Distinct Subgroup of Low-Grade Urothelial Carcinoma with High-Grade-Associated Features"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4476-2422","authenticated-orcid":false,"given":"Marc","family":"Andreu-Ingl\u00e9s","sequence":"first","affiliation":[{"name":"Department of Pathology, Hospital Universitari Sant Joan, 43204 Reus, Spain"},{"name":"Unitat de Diagn\u00f2stic Molecular, Hospital Universitari Sant Joan, 43204 Reus, Spain"},{"name":"Department of Basic Medical Sciences, Faculty of Medicine, Universitat Rovira I Virgili, 43204 Reus, Spain"},{"name":"Unitat de Recerca Biom\u00e8dica, Institut de Recerca Biom\u00e8dica de la Catalunya Sud, 43204 Reus, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9483-498X","authenticated-orcid":false,"given":"Alina-Iuliana","family":"Onoiu","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, Faculty of Medicine, Universitat Rovira I Virgili, 43204 Reus, Spain"},{"name":"Unitat de Recerca Biom\u00e8dica, Institut de Recerca Biom\u00e8dica de la Catalunya Sud, 43204 Reus, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1948-328X","authenticated-orcid":false,"given":"Marc","family":"Grifoll-Escoda","sequence":"additional","affiliation":[{"name":"Institut d\u2019Oncologia de la Catalunya Sud, 43204 Reus, Spain"},{"name":"Grup d\u2019Investigaci\u00f3 Oncol\u00f2gica, Translacional, Epidemiol\u00f2gica i Cl\u00ednica, Institut de Recerca Biom\u00e8dica de la Catalunya Sud, 43204 Reus, Spain"},{"name":"Department of Medicine and Surgery, Faculty of Medicine, Universitat Rovira I Virgili, 43204 Reus, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0954-295X","authenticated-orcid":false,"given":"Anna","family":"Hern\u00e1ndez-Aguilera","sequence":"additional","affiliation":[{"name":"Department of Pathology, Hospital Universitari Sant Joan, 43204 Reus, Spain"},{"name":"Unitat de Diagn\u00f2stic Molecular, Hospital Universitari Sant Joan, 43204 Reus, Spain"},{"name":"Department of Basic Medical Sciences, Faculty of Medicine, Universitat Rovira I Virgili, 43204 Reus, Spain"},{"name":"Unitat de Recerca Biom\u00e8dica, Institut de Recerca Biom\u00e8dica de la Catalunya Sud, 43204 Reus, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7541-9832","authenticated-orcid":false,"given":"Josep","family":"Gum\u00e0-Padr\u00f3","sequence":"additional","affiliation":[{"name":"Institut d\u2019Oncologia de la Catalunya Sud, 43204 Reus, Spain"},{"name":"Grup d\u2019Investigaci\u00f3 Oncol\u00f2gica, Translacional, Epidemiol\u00f2gica i Cl\u00ednica, Institut de Recerca Biom\u00e8dica de la Catalunya Sud, 43204 Reus, Spain"},{"name":"Department of Medicine and Surgery, Faculty of Medicine, Universitat Rovira I Virgili, 43204 Reus, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesc","family":"Riu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Hospital Universitari Sant Joan, 43204 Reus, Spain"},{"name":"Unitat de Diagn\u00f2stic Molecular, Hospital Universitari Sant Joan, 43204 Reus, Spain"},{"name":"Department of Basic Medical Sciences, Faculty of Medicine, Universitat Rovira I Virgili, 43204 Reus, Spain"},{"name":"Grup d\u2019Investigaci\u00f3 Oncol\u00f2gica, Translacional, Epidemiol\u00f2gica i Cl\u00ednica, Institut de Recerca Biom\u00e8dica de la Catalunya Sud, 43204 Reus, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karla","family":"Pe\u00f1a","sequence":"additional","affiliation":[{"name":"Department of Pathology, Hospital Universitari Sant Joan, 43204 Reus, Spain"},{"name":"Unitat de Diagn\u00f2stic Molecular, Hospital Universitari Sant Joan, 43204 Reus, Spain"},{"name":"Department of Basic Medical Sciences, Faculty of Medicine, Universitat Rovira I Virgili, 43204 Reus, Spain"},{"name":"Unitat de Recerca Biom\u00e8dica, Institut de Recerca Biom\u00e8dica de la Catalunya Sud, 43204 Reus, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3165-3640","authenticated-orcid":false,"given":"Jordi","family":"Camps","sequence":"additional","affiliation":[{"name":"Unitat de Recerca Biom\u00e8dica, Institut de Recerca Biom\u00e8dica de la Catalunya Sud, 43204 Reus, Spain"},{"name":"Department of Medicine and Surgery, Faculty of Medicine, Universitat Rovira I Virgili, 43204 Reus, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8894-2312","authenticated-orcid":false,"given":"David","family":"Parada","sequence":"additional","affiliation":[{"name":"Department of Pathology, Hospital Universitari Sant Joan, 43204 Reus, Spain"},{"name":"Unitat de Diagn\u00f2stic Molecular, Hospital Universitari Sant Joan, 43204 Reus, Spain"},{"name":"Department of Basic Medical Sciences, Faculty of Medicine, Universitat Rovira I Virgili, 43204 Reus, Spain"},{"name":"Unitat de Recerca Biom\u00e8dica, Institut de Recerca Biom\u00e8dica de la Catalunya Sud, 43204 Reus, Spain"},{"name":"Grup d\u2019Investigaci\u00f3 Oncol\u00f2gica, Translacional, Epidemiol\u00f2gica i Cl\u00ednica, Institut de Recerca Biom\u00e8dica de la 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