ArticleJournal of translational medicine2026
An integrative epigenomic and single-cell framework identifies a prognostic DNA methylation risk score and ZNF638 silencing in urothelial carcinoma.
Article in Journal of translational medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundUrothelial carcinoma (UC) exhibits profound molecular heterogeneity, yet how epigenetic dysregulation shapes tumor identity, the immune microenvironment, and clinical risk remains incompletely defined.
methodsWe integrated genome-wide DNA methylation (EM-seq, n = 72; WGBS, n = 9) with scRNA-seq (n = 9) to delineate epigenetically driven subtypes. A DNA Methylation Risk Score (DMRS) was constructed from 441 prognostic methylation haplotype blocks and validated across four independent cohorts (n = 574). Functional studies, including ZNF638 overexpression, proliferation assays, migration and invasion assays, RNA-seq, and CUT&Tag in UC cell lines, were performed to dissect downstream mechanisms of the key effector ZNF638.
resultsWe identified two methylation-defined subtypes. Methyl-high tumors displayed global hypermethylation, basal-like epithelial differentiation, and an immunosuppressive microenvironment characterized by SPP1
conclusionsDNA methylation is associated with UC heterogeneity by linking tumor cell identity, immune microenvironment remodeling, and clinical outcome. The DMRS shows potential utility for risk stratification, and ZNF638 emerges as a candidate epigenetically regulated immune-associated factor whose therapeutic relevance warrants prospective and functional validation, advancing precision medicine in UC.
trial registrationThe research was retrospectively registered (Date of Registration 2022-10-01 Registration number: ChiCTR2200064248). Ethics approval and informed consent were obtained (Peking University First Hospital, 2022SR338).
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