Please use this identifier to cite or link to this item: https://doi.org/10.1126/scitranslmed.3006086
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dc.titleGenome-wide mutational signatures of aristolochic acid and its application as a screening tool
dc.contributor.authorPoon, S.L.
dc.contributor.authorPang, S.-T.
dc.contributor.authorMcPherson, J.R.
dc.contributor.authorYu, W.
dc.contributor.authorHuang, K.K.
dc.contributor.authorGuan, P.
dc.contributor.authorWeng, W.-H.
dc.contributor.authorSiew, E.Y.
dc.contributor.authorLiu, Y.
dc.contributor.authorHeng, H.L.
dc.contributor.authorChong, S.C.
dc.contributor.authorGan, A.
dc.contributor.authorTay, S.T.
dc.contributor.authorLim, W.K.
dc.contributor.authorCutcutache, I.
dc.contributor.authorHuang, D.
dc.contributor.authorLer, L.D.
dc.contributor.authorNairismägi, M.-L.
dc.contributor.authorLee, M.H.
dc.contributor.authorChang, Y.-H.
dc.contributor.authorYu, K.-J.
dc.contributor.authorChan-On, W.
dc.contributor.authorLi, B.-K.
dc.contributor.authorYuan, Y.-F.
dc.contributor.authorQian, C.-N.
dc.contributor.authorNg, K.-F.
dc.contributor.authorWu, C.-F.
dc.contributor.authorHsu, C.-L.
dc.contributor.authorBunte, R.M.
dc.contributor.authorStratton, M.R.
dc.contributor.authorAndrew Futreal, P.
dc.contributor.authorSung, W.-K.
dc.contributor.authorChuang, C.-K.
dc.contributor.authorOng, C.K.
dc.contributor.authorRozen, S.G.
dc.contributor.authorTan, P.
dc.contributor.authorTeh, B.T.
dc.date.accessioned2014-05-20T02:29:32Z
dc.date.available2014-05-20T02:29:32Z
dc.date.issued2013-08-07
dc.identifier.citationPoon, S.L., Pang, S.-T., McPherson, J.R., Yu, W., Huang, K.K., Guan, P., Weng, W.-H., Siew, E.Y., Liu, Y., Heng, H.L., Chong, S.C., Gan, A., Tay, S.T., Lim, W.K., Cutcutache, I., Huang, D., Ler, L.D., Nairismägi, M.-L., Lee, M.H., Chang, Y.-H., Yu, K.-J., Chan-On, W., Li, B.-K., Yuan, Y.-F., Qian, C.-N., Ng, K.-F., Wu, C.-F., Hsu, C.-L., Bunte, R.M., Stratton, M.R., Andrew Futreal, P., Sung, W.-K., Chuang, C.-K., Ong, C.K., Rozen, S.G., Tan, P., Teh, B.T. (2013-08-07). Genome-wide mutational signatures of aristolochic acid and its application as a screening tool. Science Translational Medicine 5 (197) : -. ScholarBank@NUS Repository. https://doi.org/10.1126/scitranslmed.3006086
dc.identifier.issn19466234
dc.identifier.urihttp://scholarbank.nus.edu.sg/handle/10635/53439
dc.description.abstractAristolochic 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. Copyright 2013 by the American Association for the Advancement of Science.
dc.description.urihttp://libproxy1.nus.edu.sg/login?url=http://dx.doi.org/10.1126/scitranslmed.3006086
dc.sourceScopus
dc.typeArticle
dc.contributor.departmentDUKE-NUS GRADUATE MEDICAL SCHOOL S'PORE
dc.contributor.departmentCOMPUTER SCIENCE
dc.description.doi10.1126/scitranslmed.3006086
dc.description.sourcetitleScience Translational Medicine
dc.description.volume5
dc.description.issue197
dc.description.page-
dc.identifier.isiut000322819700007
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