{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T01:30:50Z","timestamp":1776216650851,"version":"3.50.1"},"reference-count":62,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T00:00:00Z","timestamp":1760054400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Bladder cancer (BC) carries a substantial global burden. Although lead (Pb) exposure has been linked to cancer, its molecular impact on bladder tumors remains unclear. We asked whether Pb-responsive transcriptional programs are present and clinically relevant in BC by integrating toxicogenomic resources with tumor transcriptomes and whether a composite lead-response score has prognostic value. Methods: Differential expression was performed on TCGA bladder urothelial carcinoma (BLCA) RNA-seq data (tumor vs. normal). Lead-associated genes were curated from the Comparative Toxicogenomics Database (CTD) and tested for over-representation among BLCA differentially expressed genes (DEGs) using a hypergeometric framework, with a stricter |log2FC| \u2265 1 sensitivity. A tumor-level lead-response score was derived from the Pb\u2013DEG overlap. Associations with overall survival (OS) were assessed using Cox models adjusted for age, sex, and pathological stage; secondary endpoints included PFI\/DFI\/DSS. Results: Lead-associated genes were significantly enriched among BLCA DEGs (background M = 20,530; K = 2618; n = 11,436; k = 1595; p = 4.21 \u00d7 10\u22129), and enrichment persisted under |log2FC| \u2265 1 (n = 4275; k = 698; p = 9.86 \u00d7 10\u221215). Pathway over-representation highlighted synaptic\/neuronal-like adhesion and transmission, MAPK-centered signaling, and cell-cycle control. Among top candidates, AQP12B was independently prognostic for OS (HR per 1 SD increase = 0.76; 95% CI 0.63\u20130.92; p = 0.0038; N = 404). The composite lead-response score showed a directionally protective but non-significant association in multivariable OS models (HR per 1 SD = 0.93; 95% CI 0.81\u20131.05; p = 0.244), while median-split Kaplan\u2013Meier (KM) curves separated (p = 0.045). Conclusions: Lead-responsive transcriptional programs are detectable in BLCA and intersect adhesion, MAPK signaling, and cell-cycle pathways. AQP12B emerges as a plausible prognostic marker, and a composite lead-response score warrants external validation for risk stratification and clinical translation.<\/jats:p>","DOI":"10.3390\/cancers17203291","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:47:08Z","timestamp":1760104028000},"page":"3291","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Lead Exposure and Bladder Cancer: Molecular Insights from TCGA RNA-Seq and Toxicogenomic Integration"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2970-1834","authenticated-orcid":false,"given":"G\u00f6zde","family":"\u00d6ztan","sequence":"first","affiliation":[{"name":"Department of Medical Biology, Istanbul Faculty of Medicine, Istanbul University, Topkap\u0131, 34093 Istanbul, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5435-706X","authenticated-orcid":false,"given":"Halim","family":"\u0130\u015fsever","sequence":"additional","affiliation":[{"name":"Department of Public Health, Istanbul Faculty of Medicine, Istanbul University, Topkap\u0131, 34093 Istanbul, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tu\u011f\u00e7e","family":"\u0130\u015fsever","sequence":"additional","affiliation":[{"name":"Turkish Health Institutes Presidency (TUSEB), 34718 Istanbul, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Levent","family":"\u015eahin","sequence":"additional","affiliation":[{"name":"Department of Labor Economics and Industrial Relations, Faculty of Economics, Istanbul University, Fatih, 34126 Istanbul, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"04109","DOI":"10.7189\/jogh.13.04109","article-title":"The global landscape of bladder cancer incidence and mortality in 2020 and projections to 2040","volume":"13","author":"Zhang","year":"2023","journal-title":"J. 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