title: Aristolochic acid-associated urothelial cancer in Taiwan.
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 unique mutational 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 TP53 mutational 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:A mutations 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.
authors.affiliation: Department of Urology,  National Taiwan University Hospital, Taipei,  Taiwan 10002.
authors.forename: Chung-Hsin
authors.initials: CH
authors.lastname: Chen
authors.forename: Kathleen G
authors.initials: KG
authors.lastname: Dickman
authors.forename: Masaaki
authors.initials: M
authors.lastname: Moriya
authors.forename: Jiri
authors.initials: J
authors.lastname: Zavadil
authors.forename: Viktoriya S
authors.initials: VS
authors.lastname: Sidorenko
authors.forename: Karen L
authors.initials: KL
authors.lastname: Edwards
authors.forename: Dmitri V
authors.initials: DV
authors.lastname: Gnatenko
authors.forename: Lin
authors.initials: L
authors.lastname: Wu
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Turesky
authors.forename: Xue-Ru
authors.initials: XR
authors.lastname: Wu
authors.forename: Yeong-Shiau
authors.initials: YS
authors.lastname: Pu
authors.forename: Arthur P
authors.initials: AP
authors.lastname: Grollman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D034341:Aristolochic Acids / Q000009:adverse effects*; D002292:Carcinoma, Renal Cell / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics; D002295:Carcinoma, Transitional Cell / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics; D018736:DNA Adducts / Q000235:genetics; D004365:Drugs, Chinese Herbal / Q000009:adverse effects*; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009153:Mutagens / Q000009:adverse effects; D009857:Oncogenes / Q000187:drug effects / Q000235:genetics; D013624:Taiwan / Q000453:epidemiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014516:Ureteral Neoplasms / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics; D019459:Urothelium / Q000187:drug effects / Q000473:pathology
chemical_list: D034341:Aristolochic Acids; D018736:DNA Adducts; D004365:Drugs, Chinese Herbal; D009153:Mutagens; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C000228:aristolochic acid I