Genome-wide mutational signatures of aristolochic acid and its application as a screening tool.
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.
NCCS-VARI Translational Research Laboratory, Division of Medical Sciences, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore.
Song Ling
SL
Poon
See-Tong
ST
Pang
John R
JR
McPherson
Willie
W
Yu
Kie Kyon
KK
Huang
Peiyong
P
Guan
Wen-Hui
WH
Weng
Ee Yan
EY
Siew
Yujing
Y
Liu
Hong Lee
HL
Heng
Soo Ching
SC
Chong
Anna
A
Gan
Su Ting
ST
Tay
Weng Khong
WK
Lim
Ioana
I
Cutcutache
Dachuan
D
Huang
Lian Dee
LD
Ler
Maarja-Liisa
ML
Nairismägi
Ming Hui
MH
Lee
Ying-Hsu
YH
Chang
Kai-Jie
KJ
Yu
Waraporn
W
Chan-On
Bin-Kui
BK
Li
Yun-Fei
YF
Yuan
Chao-Nan
CN
Qian
Kwai-Fong
KF
Ng
Ching-Fang
CF
Wu
Cheng-Lung
CL
Hsu
Ralph M
RM
Bunte
Michael R
MR
Stratton
P Andrew
PA
Futreal
Wing-Kin
WK
Sung
Cheng-Keng
CK
Chuang
Choon Kiat
CK
Ong
Steven G
SG
Rozen
Patrick
P
Tan
Bin Tean
BT
Teh
D000818:Animals; D034341:Aristolochic Acids / Q000009:adverse effects* / Q000032:analysis; D002273:Carcinogens / Q000032:analysis* / Q000633:toxicity; D045744:Cell Line, Tumor; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced; D051379:Mice; D008810:Mice, Inbred C57BL; D009153:Mutagens / Q000032:analysis / Q000633:toxicity; D009154:Mutation / Q000187:drug effects* / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics; D014571:Urologic Neoplasms / Q000235:genetics; D019459:Urothelium / Q000473:pathology
D034341:Aristolochic Acids; D002273:Carcinogens; D009153:Mutagens; C000228:aristolochic acid I