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,AQP12Bwas 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.AQP12Bemerges as a plausible prognostic marker, and a composite lead-response score warrants external validation for risk stratification and clinical translation.
**背景/目的：** 膀胱癌（BC）在全球范围内疾病负担沉重。尽管铅（Pb）暴露与癌症相关，但其对膀胱肿瘤的分子影响尚不明确。本研究旨在通过整合毒理基因组学资源与肿瘤转录组数据，探究膀胱癌中是否存在铅响应性转录程序及其临床相关性，并评估复合铅反应评分是否具有预后价值。 **方法：** 对癌症基因组图谱（TCGA）膀胱尿路上皮癌（BLCA）的RNA-seq数据（肿瘤组织 vs. 正常组织）进行差异表达分析。从比较毒理基因组学数据库（CTD）中筛选铅相关基因，并采用超几何分布框架检验其在BLCA差异表达基因（DEGs）中的富集情况，同时使用更严格的 |log2FC| ≥ 1 标准进行敏感性分析。基于铅相关基因与DEGs的交集，计算肿瘤水平的铅反应评分。采用经年龄、性别和病理分期校正的Cox模型评估其与总生存期（OS）的关联；次要终点包括无进展间期（PFI）、无病间期（DFI）和疾病特异性生存期（DSS）。 **结果：** 铅相关基因在BLCA的DEGs中显著富集（背景基因总数 M = 20,530；DEGs总数 K = 2618；铅相关基因总数 n = 11,436；交集基因数 k = 1595；p = 4.21 × 10⁻⁹），且在 |log2FC| ≥ 1 条件下富集依然显著（n = 4275；k = 698；p = 9.86 × 10⁻¹⁵）。通路富集分析突出显示了突触/神经元样粘附与传递、以MAPK为中心的信号通路以及细胞周期调控。在候选基因中，**AQP12B** 是OS的独立预后因素（每增加1个标准差的风险比 HR = 0.76；95% CI 0.63–0.92；p = 0.0038；N = 404）。在多变量OS模型中，复合铅反应评分显示出方向性保护作用但未达统计学显著性（每增加1个标准差的 HR = 0.93；95% CI 0.81–1.05；p = 0.244），而按中位数分层的Kaplan-Meier（KM）曲线则显示出差异（p = 0.045）。 **结论：** 铅响应性转录程序在BLCA中可被检测到，并涉及粘附、MAPK信号通路和细胞周期通路。**AQP12B** 可能成为一个有潜力的预后标志物，复合铅反应评分值得进行外部验证，以评估其在风险分层和临床转化中的应用价值。
Lead Exposure and Bladder Cancer: Molecular Insights from TCGA RNA-Seq and Toxicogenomic Integration
肿瘤(癌症)患者之家