Tp-53 Mutational Signature Of A Urothelial Carcinogen

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Aristolochic acid (AA), a powerful nephrotoxin and human carcinogen, was shown recently (PNAS, 102, 12129 (2007)) to be the causative agent in endemic (Balkan) nephropathy (EN). This devastating environmental disease is associated with a >50% incidence of urothelial carcinomas of the upper urinary tract (UUC). Following metabolic activation, AA reacts with genomic DNA to form covalent adducts (AL-DNA). These mutagenic lesions persist for decades in the renal cortex where they serve as robust biomarkers of exposure to AA. In EN, exposure occurs through ingestion of bread prepared from flour contaminated with AA. In China and other Asian countries, a significant fraction of the population also is exposed to AA, in this case through the medicinal use of herbal medicines prepared fr om Aristohchia plants. Such exposure, well-documented in Taiwan (JNCI, 102 1 (2009)) raises an important question: Do AA-induced cancers occur globally as a silent iatrogenic disease? To address this public health issue, we undertook a systematic study of 75 UUC patients residing in regions of Croatia, Bosnia and Serbia where EN and UUC are prevalent. DNA was obtained, with informed consent, from renal cortex and tumor tissues following nephroureterectomy. AL-DNA adducts were quantified by 32P- post-labeling techniques. Chip-sequencing technology was utilized to detect base substitutions in the TP-53 gene. Adducts were found in the renal cortex of 65% of patients with UUC. The TP53 mutation spectrum was dominated by A: TaT: A transversions located almost exclusively on the non-transcribed DNA strand. Twenty-five of these mutations occurred in exons and 12 mutations at 5′AG splice sites. Additionally, we identified several A: T aT: A mutational hotspots, including the first base of codon 131. TP53 gene mutations at this position have not previously been reported. The mechanism underlying the marked 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, for more than 50 years. Thus, AA joins vinyl chloride and aflatoxin as human chemical carcinogens with a definitive mutational signature. This information, coupled with the use of AL-DNA adducts as a biomarker, may be used to establish the role of AA ingestion in countries with a high prevalence of UUC and chronic renal disease. Importantly, public health authorities in countries where Aristolochia herbal preparations are in use should implement measures to reduce human exposure to this toxic and carcinogenic herb. (Supported by grant ES-04068 from NIEHS and the Croatian Ministry of Science) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-401.