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

## TL;DR

This study finds that lead exposure may influence bladder cancer by affecting gene activity related to cell growth and repair, potentially helping identify higher-risk patients.

## Contribution

The study identifies lead-linked genes in bladder cancer and links them to patient outcomes, suggesting potential for targeted care.

## Key findings

- Lead-associated genes are significantly enriched in bladder cancer differentially expressed genes.
- AQP12B is independently prognostic for overall survival in bladder cancer patients.
- A composite lead-response score shows a directionally protective association with survival.

## Abstract

This study examines how exposure to lead may influence bladder cancer. Using large public cancer datasets together with resources that track the health effects of lead, we analyzed patterns of gene activity in bladder tumors. We identified a group of lead-linked genes that appear more often in these cancers. These genes point to changes in how cells grow, repair themselves, and interact with neighboring cells—processes closely tied to cancer behavior. The combined pattern of lead-related genes was also linked to differences in patient outcomes, suggesting that it could help flag people at higher risk and guide more targeted care. Overall, our findings highlight the importance of considering environmental toxins, especially lead, when trying to understand bladder cancer. They provide a basis for future tests and treatments that use lead-related molecular signals to improve diagnosis and therapy.

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.