Background: Aristolochic acids (AA) and arsenic are chemical carcinogens associated with urothelial carcinogenesis. Here we investigate the combined effects of AA and arsenic toward the risk of developing upper tract urothelial carcinoma (UTUC). Methods: Hospital-based (n ¼ 89) and population-based (2,921 cases and 11,684 controls) Taiwanese UTUC cohorts were used to investigate the association between exposure to AA and/or arsenic and the risk of developing UTUC. In the hospital cohort, AA exposure was evaluated by measuring aristolactam-DNA adducts in the renal cortex and by identifying A>T TP53 mutations in tumors. In the population cohort, AA exposure was determined from prescription health insurance records. Arsenic levels were graded from 0 to 3 based on concentrations in well water and the presence of arseniasis-related diseases. Results: In the hospital cohort, 43, 26, and 20 patients resided in grade 0, 1þ2, and 3 arseniasis-endemic areas, respectively. Aristolactam-DNA adducts were present in >90% of these patients, indicating widespread AA exposure. A>T mutations in TP53 were detected in 28%, 44%, and 22% of patients residing in grade 0, 1þ2, and 3 arseniasis-endemic areas, respectively. Population studies revealed that individuals who consumed more AA-containing herbs had a higher risk of developing UTUC in both arseniasis-endemic and nonendemic areas. Logistic regression showed an additive effect of AA and arsenic exposure on the risk of developing UTUC. Conclusions: Exposure to both AA and arsenic acts additively to increase the UTUC risk in Taiwan. Impact: This is the first study to investigate the combined effect of AA and arsenic exposure on UTUC.
Bibliographical noteFunding Information:
C.-H. Chen reports grants from National Science Council, Taiwan, during the conduct of the study. Y.-S. Pu reports grants from National Science Council, Taiwan, during the conduct of the study. No disclosures were reported by the other authors.
This study was supported, in part, by a research grant (104–2314-B-002–132-) to C.-H. Chen and a research grant (104-2314-B-002-121-MY3) to Y.-S. Pu, both from the National Science Council, Taiwan. This study was also supported by grant (R01CA220367) to R.J. Turesky from the NCI and (R01ES019564) to R.J. Turesky from the National Institute of Environmental Health Sciences. Mass spectrometry was supported by Cancer Center Support Grant (CA077598) from the NCI. K. Tsai and S. Wu were recipients of Stony Brook Medicine International Research Fellowships. A.P. Grollman, V.S. Sidorenko, K. Hashimoto, M. Moriya, and K.G. Dickman gratefully acknowledge the financial support provided by Marsha and Henry Laufer.
© 2020 American Association for Cancer Research.