Nickolas Papadopoulos

Abstract 20: Whole exome sequencing of aristolochic acid induced upper urothelial carcinomas.

Abstract Aristolochic acid (AA), a human carcinogen and nephrotoxin, produced by Aristolochia plants and used extensively in traditional herbal medicines, was shown to be responsible for the clinical syndromes known as Chinese herb nephropathy and endemic (Balkan) nephropathy (EN), and to contribute to the high rate of upper urinary tract carcinoma (UUC) observed in certain Asian countries such as Taiwan. After bio-activation, AA gives rise to long-lived, pro-mutagenic aristolactam-DNA (AL-DNA) adducts that serve as specific biomarkers of exposure. Our studies of the TP53 gene in AA-induced UUC tumors detected a mutation spectrum that was dominated by A>T transversions located almost exclusively on the non-transcribed DNA strand, reflecting a failure to excise AL-DNA adducts by global genomic nucleotide excision repair. In the present study we undertook the whole exome sequencing of a set of AAN/UUC tumors from Taiwanese patients, and matching normal DNAs, to establish the genome wide consequence of AA-exposure. To establish that AA was critical in tumor formation we selected patients who had: 1) detectable AL-DNA adducts in kidney cortex DNA, and 2) the TP53 gene in tumor DNA contained an A>T mutation on the non-transcribed strand. The results indicate that these tumors indeed harbor a very high number of single base substitutions (SBS) in their coding exons (median of 545 SBS per tumor). Of these, 70% were A>T mutations with the majority of the mutated adenines on the non-transcribed strand. We are currently completing whole exome sequencing of an additional set of AA-induced UUC tumors, and ten smoking-induced UUC tumors for comparison. We will present an analysis of the driver mutations found in these tumors and the pathways harboring oncogenic mutations. Our goal is to define a panel of AA-specific mutations useful for developing biomarker screens for early detection of UUC in at risk populations. Citation Format: Thomas A. Rosenquist, Margaret Hoang, Maasaki Moriya, Victoriya S. Sidorenko, Kathleen Dickman, Chung-Hsin Chen, Lin Wu, Nickolas Papadopoulos, Yeong-Shiau Pu, Kenneth W. Kinzler, Bert Vogelstein, Arthur P. Grollman. Whole exome sequencing of aristolochic acid induced upper urothelial carcinomas. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 20.