TY - JOUR
T1 - Mutational signature of aristolochic acid exposure as revealed by whole-exome sequencing
AU - Hoang, Margaret L.
AU - Chen, Chung Hsin
AU - Sidorenko, Viktoriya S.
AU - He, Jian
AU - Dickman, Kathleen G.
AU - Yun, Byeong Hwa
AU - Moriya, Masaaki
AU - Niknafs, Noushin
AU - Douville, Christopher
AU - Karchin, Rachel
AU - Turesky, Robert J.
AU - Pu, Yeong Shiau
AU - Vogelstein, Bert
AU - Papadopoulos, Nickolas
AU - Grollman, Arthur P.
AU - Kinzler, Kenneth W.
AU - Rosenquist, Thomas A.
PY - 2013/8/7
Y1 - 2013/8/7
N2 - 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.
AB - 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.
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U2 - 10.1126/scitranslmed.3006200
DO - 10.1126/scitranslmed.3006200
M3 - Article
C2 - 23926200
AN - SCOPUS:84883894030
SN - 1946-6234
VL - 5
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 197
M1 - 197ra102
ER -
