Genome-wide mutational signatures of aristolochic acid and its application as a screening tool

• Published in: Science translational medicine Vol. 5; no. 197; p. 197ra101
• Main Authors: Poon, Song Ling, Pang, See-Tong, McPherson, John R, Yu, Willie, Huang, Kie Kyon, Guan, Peiyong, Weng, Wen-Hui, Siew, Ee Yan, Liu, Yujing, Heng, Hong Lee, Chong, Soo Ching, Gan, Anna, Tay, Su Ting, Lim, Weng Khong, Cutcutache, Ioana, Huang, Dachuan, Ler, Lian Dee, Nairismägi, Maarja-Liisa, Lee, Ming Hui, Chang, Ying-Hsu, Yu, Kai-Jie, Chan-On, Waraporn, Li, Bin-Kui, Yuan, Yun-Fei, Qian, Chao-Nan, Ng, Kwai-Fong, Wu, Ching-Fang, Hsu, Cheng-Lung, Bunte, Ralph M, Stratton, Michael R, Futreal, P Andrew, Sung, Wing-Kin, Chuang, Cheng-Keng, Ong, Choon Kiat, Rozen, Steven G, Tan, Patrick, Teh, Bin Tean
• Format: Journal Article
• Language: English
• Published: United States 07.08.2013
• Subjects: Animals; Aristolochic Acids - adverse effects; Aristolochic Acids - analysis; Carcinogens - analysis; Carcinogens - toxicity; Cell Line, Tumor; Genome, Human - genetics; Humans; Kidney Diseases - chemically induced; Mice; Mice, Inbred C57BL; Mutagens - analysis; Mutagens - toxicity; Mutation - drug effects; Mutation - genetics; Neoplasms - genetics; RNA Splicing - genetics; Urologic Neoplasms - genetics; Urothelium - pathology
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.3006086

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 (UTUC). Whole-genome and exome analysis of nine AA-associated UTUCs 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-UTUC mutational signature was characterized by A:T to T:A transversions at the sequence motif A[C|T]AGG, located primarily on nontranscribed strands. AA-induced mutations were also significantly enriched at splice sites, suggesting a role for splice-site mutations in UTUC pathogenesis. RNA sequencing of AA-UTUC 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-UTUC, 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 that were not known to be associated with AA, we screened 93 hepatocellular carcinoma genomes/exomes and identified AA-like mutational signatures in 11. Our study highlights an unusual 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.