title: Aristolactam-DNA adducts are a biomarker of environmental exposure to aristolochic acid.
abstract: Endemic (Balkan) nephropathy is a chronic tubulointerstitial disease frequently accompanied by urothelial cell carcinomas of the upper urinary tract. This disorder has recently been linked to exposure to aristolochic acid, a powerful nephrotoxin and human carcinogen. Following metabolic activation, aristolochic acid reacts with genomic DNA to form aristolactam-DNA adducts that generate a unique TP53 mutational spectrum in the urothelium. The aristolactam-DNA adducts are concentrated in the renal cortex, thus serving as biomarkers of internal exposure to aristolochic acid. Here, we present molecular epidemiologic evidence relating carcinomas of the upper urinary tract to dietary exposure to aristolochic acid. DNA was extracted from the renal cortex and urothelial tumor tissue of 67 patients that underwent nephroureterectomy for carcinomas of the upper urinary tract and resided in regions of known endemic nephropathy. Ten patients from nonendemic regions with carcinomas of the upper urinary tract served as controls. Aristolactam-DNA adducts were quantified by (32)P-postlabeling, the adduct was confirmed by mass spectrometry, and TP53 mutations in tumor tissues were identified by chip sequencing. Adducts were present in 70% of the endemic cohort and in 94% of patients with specific A:T to T:A mutations in TP53. In contrast, neither aristolactam-DNA adducts nor specific mutations were detected in tissues of patients residing in nonendemic regions. Thus, in genetically susceptible individuals, dietary exposure to aristolochic acid is causally related to endemic nephropathy and carcinomas of the upper urinary tract.
authors.affiliation: School of Medicine, University of Zagreb and Department for Nephrology, Arterial Hypertension and Dialysis, University Hospital Center Zagreb, Zagreb, Croatia.
authors.forename: Bojan
authors.initials: B
authors.lastname: Jelaković
authors.forename: Sandra
authors.initials: S
authors.lastname: Karanović
authors.forename: Ivana
authors.initials: I
authors.lastname: Vuković-Lela
authors.forename: Frederick
authors.initials: F
authors.lastname: Miller
authors.forename: Karen L
authors.initials: KL
authors.lastname: Edwards
authors.forename: Jovan
authors.initials: J
authors.lastname: Nikolić
authors.forename: Karla
authors.initials: K
authors.lastname: Tomić
authors.forename: Neda
authors.initials: N
authors.lastname: Slade
authors.forename: Branko
authors.initials: B
authors.lastname: Brdar
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Turesky
authors.forename: Želimir
authors.initials: Ž
authors.lastname: Stipančić
authors.forename: Damir
authors.initials: D
authors.lastname: Dittrich
authors.forename: Arthur P
authors.initials: AP
authors.lastname: Grollman
authors.forename: Kathleen G
authors.initials: KG
authors.lastname: Dickman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D034341:Aristolochic Acids / Q000009:adverse effects* / Q000378:metabolism; D001449:Balkan Nephropathy / Q000139:chemically induced* / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis; D001711:Biotransformation; D017522:Bosnia and Herzegovina / Q000453:epidemiology; D002274:Carcinogens, Environmental / Q000009:adverse effects* / Q000378:metabolism; D002277:Carcinoma / Q000139:chemically induced* / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D017523:Croatia / Q000453:epidemiology; D018736:DNA Adducts / Q000032:analysis*; D004252:DNA Mutational Analysis; D004032:Diet; D004781:Environmental Exposure; D004784:Environmental Monitoring / Q000379:methods; D062665:Epidemiological Monitoring; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007672:Kidney Cortex / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D017720:Molecular Epidemiology; D009154:Mutation; D012111:Residence Characteristics; D018570:Risk Assessment; D012307:Risk Factors; D055771:Serbia / Q000453:epidemiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014571:Urologic Neoplasms / Q000139:chemically induced* / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism
chemical_list: D034341:Aristolochic Acids; D015415:Biomarkers; D002274:Carcinogens, Environmental; D018736:DNA Adducts; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C000228:aristolochic acid I
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