title: Evidence of exposure to aristolochic acid in patients with urothelial cancer from a Balkan endemic nephropathy region of Romania.
abstract: Recently, chronic Aristolochia poisoning was found responsible for the aetiology of Balkan endemic nephropathy (BEN) in Croatia, Serbia, and Bosnia, and diet was the likely route of exposure to aristolochic acid (AA). BEN, often associated with an increased incidence of upper urinary tract carcinoma (UUC), also affects residents of certain rural villages in Romania. AA is a nephrotoxin and human carcinogen that forms DNA adducts after metabolic activation, which induce characteristic TP53 mutations in urothelial tumours. Here we present the first evidence linking AA exposure to UUC in residents of an endemic region in the Romanian Mehedinti County. DNA was extracted from kidney and tumour tissue of seven patients who underwent nephroureterectomy for UUC and resided in BEN villages (endemic group). Five patients with UUC from nonendemic villages served as controls. AA-DNA adducts (7-(deoxyadenosin-N(6) -yl)-aristolactam I), established biomarkers of AA exposure, were identified by (32)P-postlabelling in renal DNA of six patients from the endemic group and in one of the nonendemic group (adduct levels ranged from 0.3 to 6.5 adducts per 10(8) nucleotides). Additionally, an A to T transversion in TP53, a base substitution characteristic of AA mutagenic activity was found in urothelial tumour DNA of one patient from the endemic group. Our results provide a molecular link to the cause of urothelial tumours in BEN regions of Romania indicating that AA is the common aetiological agent for BEN across its numerous geographical foci.
authors.affiliation: Research Group Genetic Alterations in Carcinogenesis, German Cancer Research Center, Heidelberg, Germany. h.schmeiser@dkfz.de
authors.forename: Heinz H
authors.initials: HH
authors.lastname: Schmeiser
authors.forename: Jill E
authors.initials: JE
authors.lastname: Kucab
authors.forename: Volker M
authors.initials: VM
authors.lastname: Arlt
authors.forename: David H
authors.initials: DH
authors.lastname: Phillips
authors.forename: Monica
authors.initials: M
authors.lastname: Hollstein
authors.forename: Gheorghe
authors.initials: G
authors.lastname: Gluhovschi
authors.forename: Cristina
authors.initials: C
authors.lastname: Gluhovschi
authors.forename: Mirela
authors.initials: M
authors.lastname: Modilca
authors.forename: Liviu
authors.initials: L
authors.lastname: Daminescu
authors.forename: Ligia
authors.initials: L
authors.lastname: Petrica
authors.forename: Silvia
authors.initials: S
authors.lastname: Velciov
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D034341:Aristolochic Acids / Q000633:toxicity*; D001449:Balkan Nephropathy; D018736:DNA Adducts / Q000187:drug effects / Q000235:genetics; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D012383:Romania; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000209:etiology*
chemical_list: D034341:Aristolochic Acids; D018736:DNA Adducts; D016159:Tumor Suppressor Protein p53