Carcinogenesis Advance Access originally published online on April 13, 2007
Carcinogenesis 2007 28(11):2253-2261; 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, SM2 5NG, UK
1 Department of Biochemistry, Faculty of Science, Charles University, 12840 Prague 2, Czech Republic
2 Division of Molecular Toxicology, German Cancer Research Center, D-69120 Heidelberg, Germany
3 Department of Medicine, Guys Hospital and Kings College, London, SE1 9RT, UK
4 Department of Nephrology, Academic Erasme Hospital, 1070 Brussels, Belgium
5 Division of Genetic Alterations in Carcinogenesis, German Cancer Research Center, D-69120 Heidelberg, Germany
6 Present address: Light Laboratories, University of Leeds, Faculty of Medicine and Health, Leeds, LS2 9JT, UK
* 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 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.
Abbreviations: AA, aristolochic acid; AAN, aristolochic acid nephropathy; BEN, Balkan endemic nephropathy; CHN, Chinese herbs nephropathy; dA-AAI, 7-(deoxyadenosin-N6-yl)aristolactam I; Hupki, human p53 knock-in; IARC, International Agency for Research on Cancer; MF, mutant frequency; NQO1, NAD(P)H:quinone oxidoreductase; OTA, ochratoxin A; PAH, polycyclic aromatic hydrocarbon
Received March 1, 2007; revised March 29, 2007; accepted April 2, 2007.
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