engleski

p53 mutational signature of aristolochic acid in the upper urinary tract carcinomas

Endemic (Balkan) nephropathy (EN), a chronic renal disease affecting residents of rural villages situated near tributaries of Danube river, is strongly associated with cancers of the upper urinary tract (UUC). Hypothesis: (i) Dietary ingestion of aristolochic acid (AA), which after metabolic activation forms covalent DNA adducts in renal cortex and urothelial tissues, accounts, in conjunction with individual genetic susceptibility, for all epidemiologic and clinical features of EN/UUC ; (ii) 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. Methods: DNA was obtained from renal cortex and urothelial tumor tissues following nephroureterectomy of patients with EN/UUC. Aristolactam-DNA adducts were quantified in renal cortex by 32P-post-labeling techniques. Chip-sequencing technology was used to detect base substitutions in the p53 gene in urothelial tumor tissues. Results: (i) Aristolactam-DNA adducts were detected in the renal cortex where persist for extended period of time (up to 50 years) ;

aristolochic acid; TP53; signature mutation; urothelial cancer; Balkan endemic nephropathy

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