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

Area of Science:

• Oncology
• Environmental Health
• Toxicogenomics

Background:

• Bladder cancer (BC) presents a significant global health challenge.
• The molecular mechanisms linking lead (Pb) exposure to BC remain largely unexplored.
• Investigating Pb-responsive gene expression in BC is crucial for understanding disease pathogenesis and identifying biomarkers.

Purpose of the Study:

• To determine if lead-responsive transcriptional programs exist in bladder cancer.
• To assess the clinical relevance and prognostic value of these programs.
• To evaluate a composite lead-response score for risk stratification in BC.

Main Methods:

• Differential gene expression analysis of TCGA bladder urothelial carcinoma (BLCA) RNA-seq data.
• Curated lead-associated genes from CTD were tested for enrichment among BLCA differentially expressed genes (DEGs).
• A tumor-level lead-response score was calculated, and its association with overall survival (OS) was assessed using Cox models.

Main Results:

• Significant enrichment of lead-associated genes was found in BLCA DEGs (p < 10^-9).
• Key pathways identified include synaptic/neuronal-like adhesion, MAPK signaling, and cell-cycle control.
• AQP12B was identified as an independent prognostic marker for OS (p = 0.0038); the lead-response score showed a trend towards prognostic value (p = 0.045).

Conclusions:

• Lead-responsive transcriptional programs are present in bladder cancer, impacting adhesion, MAPK signaling, and cell-cycle pathways.
• AQP12B shows promise as a prognostic biomarker for bladder cancer.
• A composite lead-response score requires further validation for clinical application in risk stratification.