TP53 Mutational Signature of Aristolochic in Carcinomas of the Upper Urinary Tract

Endemic (Balkan) nephropathy (EN), a chronic renal disease affecting residents of rural villages situated near tributaries of Danube River, is strongly associated with transitional cell (urothelial) carcinoma of the upper urinary tract (UUC). Aristolochic acid (AA), a powerful nephrotoxin and human carcinogen, was shown recently to be the causative agent in EN. In EN, exposure occurs through ingestion of bread prepared from flour contaminated with AA. After metabolic activation AA forms covalent DNA adducts in renal cortex and urothelial tissues. Aristolactam-DNA adducts generate unique mutational spectra in p53 tumor suppressor gene, which together with the presence of DNA adducts in the renal cortex serve as biomarkers for aristolochic acid nephropathy and associated urothelial carcinomas. TP53 mutation spectrum was dominated by A:T→T:A transversions located almost exclusively on the non-transcribed DNA strand with unique „hot spots“ at several splice sites and at codons 131 and 209. TP53 gene mutations at this position have not previously been reported. The mechanism underlying the observed strand bias appears to be a selective failure to excise AL-DNA adducts by global genomic nucleotide excision repair. This factor also may account for the remarkable persistence of these adducts in human tissues (in some cases more than 50 years). In summary, aristolochic acid joins vinyl chloride and aflatoxin as human chemical carcinogens with a definitive mutational signature. This important information, coupled with the use of AL-DNA adducts as a biomarker, should prove useful in establishing the role of AA ingestion in countries with a high prevalence of UUC.