title: TP53 Mutational signature for aristolochic acid: an environmental carcinogen.
abstract: This study was designed to establish the TP53 mutational spectrum of aristolochic acid (AA), examined in the context of endemic (Balkan) nephropathy, an environmental disease associated with transitional cell (urothelial) carcinomas of the upper urinary tract (UUC). Tumor tissue was obtained from residents of regions in Bosnia, Croatia and Serbia where endemic nephropathy has been prevalent for over 50 years. Fifty-nine TP53 mutations were detected in 42 of the 97 tumors analyzed. Mutational spectra were dominated by A:T to T:A transversions with the mutated adenines located almost exclusively on the nontranscribed strand. This marked strand bias is attributed to selective processing of aristolactam-dA adducts by transcription-coupled nucleotide excision repair. Hotspots for A:T to T:A mutations include codons 131 and 179 and the 5'-AG acceptor splice site of intron 6. The unique TP53 mutational signature for AA identified in this study can be used to explore the hypothesis that botanical products containing this human carcinogen and nephrotoxin are responsible, in part, for the high prevalence of UUC and chronic renal disease in countries where Aristolochia herbal remedies traditionally have been used for medicinal purposes.
authors.affiliation: Laboratory of Chemical Biology, Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Moriya
authors.forename: Neda
authors.initials: N
authors.lastname: Slade
authors.forename: Branko
authors.initials: B
authors.lastname: Brdar
authors.forename: Zvonimir
authors.initials: Z
authors.lastname: Medverec
authors.forename: Karla
authors.initials: K
authors.lastname: Tomic
authors.forename: Bojan
authors.initials: B
authors.lastname: Jelaković
authors.forename: Lin
authors.initials: L
authors.lastname: Wu
authors.forename: Sim
authors.initials: S
authors.lastname: Truong
authors.forename: Andrea
authors.initials: A
authors.lastname: Fernandes
authors.forename: Arthur P
authors.initials: AP
authors.lastname: Grollman
mesh_terms: D034341:Aristolochic Acids / Q000008:administration & dosage / Q000633:toxicity*; D002274:Carcinogens, Environmental / Q000633:toxicity*; D002295:Carcinoma, Transitional Cell / Q000235:genetics; D004032:Diet; D016158:Genes, p53; D006801:Humans; D009154:Mutation; D019459:Urothelium
chemical_list: D034341:Aristolochic Acids; D002274:Carcinogens, Environmental