Abstract
Occupational exposure to the arylamines benzidine and β-naphthylamine increase bladder cancer risk up to 100-fold, making them some of the most powerful human carcinogens. We hypothesize that tumors arising in people with occupational exposures have different patterns of gene expression than histologically similar tumors from people without such exposures. In a case-case study, we compare gene expression in 22 formalin-fixed paraffin-embedded (FFPE) bladder tumors from men with high-level occupational exposure to arylamines to that in 26 FFPE bladder tumors from men without such exposure. Gene expression analysis was performed on the NanoString nCounter system using a PanCancer Progression Panel comprised of 740 cancer progression-related genes and a custom panel of 69 arylamine- and bladder cancer-related genes which were chosen from in vitro studies. Although fold differences were small, there was evidence of differential expression by exposure status for 17 genes from the Progression Panel and 4 genes from the custom panel. In total, 10 genes showed dose-response association at a p < 0.01, of which 4 genes (CD46, NR4A1, BAX, and YWHAZ) passed a false discovery rate (FDR) q value cutoff of 0.05 but were not significant after Bonferroni correction. Overall, we find limited evidence for differentially expressed genes in pathways related to DNA damage signaling and epithelial-to-mesenchymal transition (EMT).
Highlights
Bladder cancer is the sixth most common type of cancer in the United States with an estimated 81,400 new cases in 2020 [1, 2]
Bladder cancer in workers occupationally exposed to arylamines has been investigated since the early 1900s, with substantial risks established in epidemiologic studies dating back to the 1950s [4, 7,8,9]
In vitro and in vivo exposure studies have evaluated gene expression changes associated with acute arylamine exposure [19, 20, 21, 23], whereas human occupation studies have often used blood DNA samples to examine genetic susceptibility and used tumor DNA samples to search for exposure-specific mutation signatures [22, 31,32,33,34,35]
Summary
Bladder cancer is the sixth most common type of cancer in the United States with an estimated 81,400 new cases in 2020 [1, 2]. Occupational exposure to arylamines used in the production of azo dyes for paper, textile, and leather industries is one of the most powerful examples of human chemical carcinogenesis [4,5,6,7,8,9], raising bladder cancer risks up to 100-fold [10, 11]. In addition to occupational exposures, arylamines are one of the many carcinogenic compounds found in tobacco smoke [12, 13], with cigarette smoking increasing bladder cancer risk 2- to 3-fold [14, 15]. Exposure of human uroepithelial and bladder cancer cell lines leads to induction of genes involved in epithelial-to-mesenchymal transition (EMT) [20, 21]. We have previously investigated p53 mutational patterns in bladder tumors from men with occupational exposure to arylamines compared to tumors from men without such
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