Arsenic-endemic regions correlate with elevated tumor mutational burden and genomic alterations in urothelial carcinoma

Purpose: Urothelial carcinoma includes upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB). In Taiwan, the incidence of UTUC is disproportionately high. Environmental carcinogens such as arsenic may contribute to this pattern. This study aimed to evaluate the association of arsenic-endemic regions with tumor mutational burden (TMB) and genomic alterations in both UTUC and UCB patients. Materials and methods: We retrospectively analyzed 67 urothelial carcinoma patients who underwent surgical resection or biopsy followed by next-generation sequencing at our institution between 2018 and 2023. Clinical data included demographics, tumor stage, and residential location. Arsenic-endemic regions were defined based on official Groundwater Pollution Control Standards where >75% probability of arsenic concentration exceeded 0.025 mg/L. TMB was calculated as nonsynonymous mutations per megabase, with TMB-high defined as ≥10/Mb. Genetic alterations were annotated using catalogue of somatic mutations in cancer, ClinVar, and in-house databases. Results: Among 67 patients, 41 (61.2%) had UTUC and 26 (38.8%) had UCB. TMB-high was observed in 35 patients (52.2%). Patients from endemic areas had significantly higher TMB compared with those from nonendemic regions (UTUC: 12.5 vs 6.3/Mb, P = .033; UCB: 10.0 vs 5.0/Mb, P = .039). TMB-high tumors were enriched for mutations in KDM6A, TSC1, and PIK3CA, whereas STK11 mutations were observed only in TMB-low tumors. Distinct mutational landscapes were identified between UTUC and UCB, with UTUC characterized by frequent TP53, KMT2D, and KDM6A alterations. Conclusion: Arsenic-endemic regions in Taiwan correlate with elevated TMB and distinct genomic alterations in urothelial carcinoma. These findings highlight the impact of environmental carcinogens on urothelial carcinoma mutagenesis and support the integration of genomic profiling into risk assessment and precision oncology strategies for patients in endemic areas.