Mutational signature of aristolochic acid exposure as revealed by whole-exome sequencing

Margaret L. Hoang, Chung Hsin Chen, Viktoriya S. Sidorenko, Jian He, Kathleen G. Dickman, Byeong Hwa Yun, Masaaki Moriya, Noushin Niknafs, Christopher Douville, Rachel Karchin, Robert J. Turesky, Yeong Shiau Pu, Bert Vogelstein, Nickolas Papadopoulos, Arthur P. Grollman, Kenneth W. Kinzler, Thomas A. Rosenquist

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Abstract

In humans, exposure to aristolochic acid (AA) is associated with urothelial carcinoma of the upper urinary tract (UTUC). Exome sequencing of UTUCs from 19 individuals with documented exposure to AA revealed a remarkably large number of somatic mutations and an unusual mutational signature attributable to AA. Most of the mutations (72%) in these tumors were A:T-to-T:A transversions, located predominantly on the nontranscribed strand, with a strong preference for deoxyadenosine in a consensus sequence (T/CAG). This trinucleotide motif overlaps the canonical splice acceptor site, possibly accounting for the excess of splice site mutations observed in these tumors. The AA mutational fingerprint was found frequently in oncogenes and tumor suppressor genes in AA-associated UTUC. The AA mutational signature was observed in one patient's tumor from a UTUC cohort without previous indication of AA exposure. Together, these results directly link an established environmental mutagen to cancer through genome-wide sequencing and highlight its power to reveal individual exposure to carcinogens.

Original languageEnglish (US)
Article number197ra102
JournalScience Translational Medicine
Volume5
Issue number197
DOIs
StatePublished - Aug 7 2013

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Hoang, M. L., Chen, C. H., Sidorenko, V. S., He, J., Dickman, K. G., Yun, B. H., Moriya, M., Niknafs, N., Douville, C., Karchin, R., Turesky, R. J., Pu, Y. S., Vogelstein, B., Papadopoulos, N., Grollman, A. P., Kinzler, K. W., & Rosenquist, T. A. (2013). Mutational signature of aristolochic acid exposure as revealed by whole-exome sequencing. Science Translational Medicine, 5(197), [197ra102]. https://doi.org/10.1126/scitranslmed.3006200