Skip to main content
release_alert
Welcome to the new Scholars 3.0! Read about new features and let us know what you think.
cancel

Genome-wide mutational signatures of aristolochic acid and its application as a screening tool.

Publication ,  Journal Article
Poon, SL; Pang, S-T; McPherson, JR; Yu, W; Huang, KK; Guan, P; Weng, W-H; Siew, EY; Liu, Y; Heng, HL; Chong, SC; Gan, A; Tay, ST; Lim, WK ...
Published in: Sci Transl Med
August 7, 2013

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

August 7, 2013

Volume

5

Issue

197

Start / End Page

197ra101

Location

United States

Related Subject Headings

  • Urothelium
  • Urologic Neoplasms
  • RNA Splicing
  • Neoplasms
  • Mutation
  • Mutagens
  • Mice, Inbred C57BL
  • Mice
  • Kidney Diseases
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Poon, S. L., Pang, S.-T., McPherson, J. R., Yu, W., Huang, K. K., Guan, P., … Teh, B. T. (2013). Genome-wide mutational signatures of aristolochic acid and its application as a screening tool. Sci Transl Med, 5(197), 197ra101. https://doi.org/10.1126/scitranslmed.3006086
Poon, Song Ling, See-Tong Pang, John R. McPherson, Willie Yu, Kie Kyon Huang, Peiyong Guan, Wen-Hui Weng, et al. “Genome-wide mutational signatures of aristolochic acid and its application as a screening tool.Sci Transl Med 5, no. 197 (August 7, 2013): 197ra101. https://doi.org/10.1126/scitranslmed.3006086.
Poon SL, Pang S-T, McPherson JR, Yu W, Huang KK, Guan P, et al. Genome-wide mutational signatures of aristolochic acid and its application as a screening tool. Sci Transl Med. 2013 Aug 7;5(197):197ra101.
Poon, Song Ling, et al. “Genome-wide mutational signatures of aristolochic acid and its application as a screening tool.Sci Transl Med, vol. 5, no. 197, Aug. 2013, p. 197ra101. Pubmed, doi:10.1126/scitranslmed.3006086.
Poon SL, Pang S-T, McPherson JR, Yu W, Huang KK, Guan P, Weng W-H, Siew EY, Liu Y, Heng HL, Chong SC, Gan A, Tay ST, Lim WK, Cutcutache I, Huang D, Ler LD, Nairismägi M-L, Lee MH, 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 RM, Stratton MR, Futreal PA, Sung W-K, Chuang C-K, Ong CK, Rozen SG, Tan P, Teh BT. Genome-wide mutational signatures of aristolochic acid and its application as a screening tool. Sci Transl Med. 2013 Aug 7;5(197):197ra101.

Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

August 7, 2013

Volume

5

Issue

197

Start / End Page

197ra101

Location

United States

Related Subject Headings

  • Urothelium
  • Urologic Neoplasms
  • RNA Splicing
  • Neoplasms
  • Mutation
  • Mutagens
  • Mice, Inbred C57BL
  • Mice
  • Kidney Diseases
  • Humans