LINE-1 DNA methylation mediates smoking-related risk in site-specific urothelial carcinoma: a Taiwan case-control study.

While environmental and lifestyle factors contribute to urothelial carcinoma (UC) development, their differential effects on bladder cancer (UB) versus upper tract urothelial carcinoma (UTUC) and the underlying epigenetic mechanisms remain unclear. This study investigated location-specific risk factors and the mediating role of LINE-1 DNA methylation in UC carcinogenesis. A hospital-based case-control study was conducted, comprising 478 UC cases (266 UB, 204 UTUC) and 569 controls. The risk factors, including smoking, Chinese herbal medicine use, comorbidities, and blood levels of arsenic, cadmium, and lead, were assessed through questionnaires and blood sample analysis. LINE-1 DNA methylation levels were measured by pyrosequencing. LASSO regression for variable selection and logistic regression for risk assessment. Mediation analysis was performed to evaluate the role of LINE-1 DNA methylation in the relationship between environmental exposures and UC risk. UB risk was associated with male sex, smoking, chronic kidney disease (CKD), elevated blood arsenic, and diabetes (all p < 0.0001), while UTUC risk was primarily linked to female sex (p = 0.0004) and CKD (p < 0.0001). LINE-1 hypermethylation was associated with both UB and UTUC risk (p < 0.0001). Notably, LINE-1 methylation significantly mediated the relationship between smoking and UC risk, particularly in males, while no significant mediation was observed for other exposures. This study demonstrates distinct risk profiles for UB and UTUC, and identifies LINE-1 methylation as a key mediator in smoking-related UC risk, especially in men. These findings suggest the need for location-specific prevention strategies and highlight the importance of epigenetic mechanisms in UC development.