Mutational signature of aristolochic acid exposure as revealed by whole-exome sequencing.
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.
Ludwig Center for Cancer Genetics and Therapeutics and the Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
Margaret L
ML
Hoang
Chung-Hsin
CH
Chen
Viktoriya S
VS
Sidorenko
Jian
J
He
Kathleen G
KG
Dickman
Byeong Hwa
BH
Yun
Masaaki
M
Moriya
Noushin
N
Niknafs
Christopher
C
Douville
Rachel
R
Karchin
Robert J
RJ
Turesky
Yeong-Shiau
YS
Pu
Bert
B
Vogelstein
Nickolas
N
Papadopoulos
Arthur P
AP
Grollman
Kenneth W
KW
Kinzler
Thomas A
TA
Rosenquist
D000368:Aged; D034341:Aristolochic Acids / Q000009:adverse effects*; D059472:Exome / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000187:drug effects* / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014571:Urologic Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D019459:Urothelium / Q000473:pathology
D034341:Aristolochic Acids; C000228:aristolochic acid I