Carcinogenesis Advance Access published online on April 13, 2007
Carcinogenesis, doi:10.1093/carcin/bgm082
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Aristolochic acid mutagenesis: molecular clues to the aetiology of Balkan endemic nephropathy-associated urothelial cancer
Section of Molecular Carcinogenesis, Institute of Cancer Research, Sutton, Surrey, UK
1 Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic
2 Division of Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany
3 Department of Medicine, Guys Hospital and Kings College, London, UK
4 Department of Nephrology, Academic Erasme Hospital, Brussels, Belgium
5 Division of Genetic Alterations in Carcinogenesis, German Cancer Research Center, Heidelberg, Germany
* To whom correspondence should be addressed. Tel: +44 208 722 4405; Fax: +44 208 722 4052; Email: volker.arlt{at}icr.ac.uk
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 a new approach to investigate AA-induced mutagenesis in BEN that may 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 clearer link between urothelial tumours, p53 mutations and AA exposure should emerge as more tumour DNA from BEN patients becomes available for mutation analysis. We predict that the observed p53 mutation spectrum will be dominated by AT
TA transversion mutations as it has already been demonstrated in the human p53 gene of immortalized cells after exposure to aristolochic acid I. Moreover, the detection of AA-specific DNA adducts in a number of patients with end-stage renal disease and upper urinary tract malignancy coming from areas endemic for BEN also supports the hypothesis that chronic exposure to AA is a risk factor for BEN and its associated cancer.
Key Words: aristolochic acid • Balkan endemic nephropathy • p53 • urothelial cancer • mutations • DNA adducts
Received March 1, 2007; revised March 29, 2007; accepted April 2, 2007.
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