Aristolochic acid-associated urothelial cancer in Taiwan

Chung Hsin Chen, Kathleen G. Dickman, Masaaki Moriya, Jiri Zavadil, Viktoriya S. Sidorenko, Karen L. Edwards, Dmitri V. Gnatenko, Lin Wu, Robert J. Turesky, Xue Ru Wu, Yeong Shiau Pu, Arthur P. Grollman

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Abstract

Aristolochic acid, a potent human carcinogen produced by Aristolochia plants, is associated with urothelial carcinoma of the upper urinary tract (UUC). Following metabolic activation, aristolochic acid reacts with DNA to form aristolactam (AL)-DNA adducts. These lesions concentrate in the renal cortex, where they serve as a sensitive and specific biomarker of exposure, and are found also in the urothelium,where they give rise to a uniquemutational signature in the TP53 tumor-suppressor gene. Using AL-DNA adducts and TP53 mutation spectra as biomarkers,we conducted a molecular epidemiologic study of UUC in Taiwan, where the incidence of UUC is the highest reported anywhere in the world and where Aristolochia herbal remedies have been used extensively for many years. Our study involves 151 UUC patients, with 25 patients with renal cell carcinomas serving as a control group. The TP53mutational signature in patients with UUC, dominated by otherwise rare A:T to T:A transversions, is identical to that observed in UUC associated with Balkan endemic nephropathy, an environmental disease. Prominent TP53 mutational hotspots include the adenine bases of 5′AG (acceptor) splice sites located almost exclusively on the nontranscribed strand. A:T to T:Amutations also were detected at activating positions in the FGFR3 and HRAS oncogenes. AL-DNA adducts were present in the renal cortex of 83% of patients with A:T to T:A mutations in TP53, FGFR3, or HRAS. We conclude that exposure to aristolochic acid contributes significantly to the incidence of UUC in Taiwan, a finding with significant implications for global public health.

Original languageEnglish (US)
Pages (from-to)8241-8246
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number21
DOIs
StatePublished - May 22 2012

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Keywords

  • DNA damage
  • Herbal medicine
  • Traditional Chinese medicine
  • Transitional cell carcinoma
  • Upper urinary tract carcinoma

Cite this

Chen, C. H., Dickman, K. G., Moriya, M., Zavadil, J., Sidorenko, V. S., Edwards, K. L., Gnatenko, D. V., Wu, L., Turesky, R. J., Wu, X. R., Pu, Y. S., & Grollman, A. P. (2012). Aristolochic acid-associated urothelial cancer in Taiwan. Proceedings of the National Academy of Sciences of the United States of America, 109(21), 8241-8246. https://doi.org/10.1073/pnas.1119920109