Lead Exposure and Bladder Cancer: Molecular Insights from TCGA RNA-Seq and Toxicogenomic Integration

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| ≥ 1 sensitivity. A tumor-level lead-response score was derived from the Pb-DEG 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 × 10^-9), and enrichment persisted under |log₂FC| ≥ 1 (n = 4275; k = 698; p = 9.86 × 10^-15). 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 0.63-0.92; 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 0.81-1.05; p = 0.244), while median-split Kaplan-Meier (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.