Abstract
Abstract Aristolochic acid (AA), a natural product of Aristolochia plants found in herbal remedies and health supplements, is a Group 1 carcinogen that can cause nephrotoxicity and upper urinary tract urothelial cell carcinoma (UCC). Whole genome and exome analysis of 9 AA-associated UCCs revealed a strikingly high somatic mutation rate (150 mutations/Mb), exceeding smoking-associated lung cancer (8 mutations/Mb) and ultraviolet radiation-associated melanoma (111 mutations/Mb). The AA-UCC mutational signature was characterized by A:T to T:A transversions at the sequence motif A[C|T]AGG, located primarily on non-transcribed strands. AA-induced mutations were also significantly enriched at splice sites, suggesting a role for splice site mutations in UCC pathogenesis. RNA sequencing of AA-UCC confirmed a general up-regulation of nonsense-mediated decay machinery components and aberrant splicing events associated with splice site mutations. We observed a high frequency of somatic mutations in chromatin modifiers, particularly KDM6A, in AA-UCC, and demonstrated the sufficiency of AA to induce renal dysplasia in mice and reproduced the AA mutational signature in experimentally treated human renal tubular cells. Finally, exploring other malignancies not previously associated with AA, we screened 93 hepatocellular carcinoma genomes/exomes and identified AA-like mutational signatures in eleven. Our study highlights a unique genome-wide AA mutational signature, and the potential use of mutation signatures as “molecular fingerprints” for interrogating high-throughput cancer genome data, to infer previous carcinogen exposures. Citation Format: Song Ling Poon, See-Tong Pang, John R. McPherson, Steven G. Rozen, Patrick Tan, Bin Tean Teh. The use of mutational signatures in identifying carcinogen exposure. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4270. doi:10.1158/1538-7445.AM2014-4270
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