title: Aristolochic acid mutagenesis: molecular clues to the aetiology of Balkan endemic nephropathy-associated urothelial cancer.
abstract: Balkan endemic nephropathy (BEN) is found in certain rural areas of the Balkans and affects at least 25,000 inhabitants. Of the many hypotheses on BEN, the Aristolochia hypothesis has recently gained ground substantiated by the investigations on aristolochic acid nephropathy (AAN). On both clinical and morphological grounds, AAN is very similar to BEN. That exposure to aristolochic acid (AA) of individuals living in endemic areas through consumption of bread made with flour contaminated with seeds of Aristolochia clematitis is responsible for BEN is an old hypothesis, but one which is fully consistent with the unique epidemiologic features of BEN. Here, we propose an approach to investigate AA-induced mutagenesis in BEN that can provide molecular clues to the aetiology of its associated urothelial cancer. The molecular mechanism of AA-induced carcinogenesis demonstrates a strong association between DNA adduct formation, mutation pattern and tumour development. A clear link between urothelial tumours, p53 mutations and AA exposure should emerge as more tumour DNA from BEN patients from different endemic areas becomes available for mutation analysis. We predict that the observed p53 mutation spectrum will be dominated by AT --> TA transversion mutations as has already been demonstrated in the human p53 gene of immortalized cells after exposure to AAI and urothelial tumours from BEN patients in Croatia. Moreover, the detection of AA-specific DNA adducts in renal tissue of a number of BEN patients and individuals living in areas endemic for BEN in Croatia provides new evidence that chronic exposure to AA is a risk factor for BEN and its associated cancer.
authors: Section of Molecular Carcinogenesis, Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK. volker.arlt@icr.ac.uk
authors: Volker M
authors: VM
authors: Arlt
authors: Marie
authors: M
authors: Stiborová
authors: Jochen
authors: J
authors: vom Brocke
authors: Maria L
authors: ML
authors: Simões
authors: Graham M
authors: GM
authors: Lord
authors: Joelle L
authors: JL
authors: Nortier
authors: Monica
authors: M
authors: Hollstein
authors: David H
authors: DH
authors: Phillips
authors: Heinz H
authors: HH
authors: Schmeiser
mesh_terms: D000818:Animals; D034341:Aristolochic Acids / Q000633:toxicity*; D001449:Balkan Nephropathy / Q000139:chemically induced* / Q000150:complications; D002471:Cell Transformation, Neoplastic; D018736:DNA Adducts / Q000378:metabolism; D016158:Genes, p53; D006801:Humans; D016296:Mutagenesis; D009153:Mutagens / Q000633:toxicity*; D001749:Urinary Bladder Neoplasms / Q000150:complications* / Q000378:metabolism
chemical_list: D034341:Aristolochic Acids; D018736:DNA Adducts; D009153:Mutagens; C000228:aristolochic acid I