title: Mutation signatures implicate aristolochic acid in bladder cancer development.
abstract: BACKGROUND
  Aristolochic acid (AA) is a natural compound found in many plants of the Aristolochia genus, and these plants are widely used in traditional medicines for numerous conditions and for weight loss. Previous work has connected AA-mutagenesis to upper-tract urothelial cell carcinomas and hepatocellular carcinomas. We hypothesize that AA may also contribute to bladder cancer.
  
  
  METHODS
  Here, we investigated the involvement of AA-mutagenesis in bladder cancer by sequencing bladder tumor genomes from two patients with known exposure to AA. After detecting strong mutational signatures of AA exposure in these tumors, we exome-sequenced and analyzed an additional 11 bladder tumors and analyzed publicly available somatic mutation data from a further 336 bladder tumors.
  
  
  RESULTS
  The somatic mutations in the bladder tumors from the two patients with known AA exposure showed overwhelming AA signatures. We also detected evidence of AA exposure in 1 out of 11 bladder tumors from Singapore and in 3 out of 99 bladder tumors from China. In addition, 1 out of 194 bladder tumors from North America showed a pattern of mutations that might have resulted from exposure to an unknown mutagen with a heretofore undescribed pattern of A > T mutations. Besides the signature of AA exposure, the bladder tumors also showed the CpG > TpG and activated-APOBEC signatures, which have been previously reported in bladder cancer.
  
  
  CONCLUSIONS
  This study demonstrates the utility of inferring mutagenic exposures from somatic mutation spectra. Moreover, AA exposure in bladder cancer appears to be more pervasive in the East, where traditional herbal medicine is more widely used. More broadly, our results suggest that AA exposure is more extensive than previously thought both in terms of populations at risk and in terms of types of cancers involved. This appears to be an important public health issue that should be addressed by further investigation and by primary prevention through regulation and education. In addition to opportunities for primary prevention, knowledge of AA exposure would provide opportunities for secondary prevention in the form of intensified screening of patients with known or suspected AA exposure.
authors.affiliation: Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610 Singapore ; Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857 Singapore.
authors.forename: Song Ling
authors.initials: SL
authors.lastname: Poon
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857 Singapore ; Centre for Computational Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857 Singapore.
authors.forename: Mi Ni
authors.initials: MN
authors.lastname: Huang
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857 Singapore ; Centre for Computational Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857 Singapore.
authors.forename: Yang
authors.initials: Y
authors.lastname: Choo
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857 Singapore ; Centre for Computational Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857 Singapore.
authors.forename: John R
authors.initials: JR
authors.lastname: McPherson
authors.affiliation: Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610 Singapore ; Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857 Singapore ; National University of Singapore, Graduate School for Integrative Sciences and Engineering, 28 Medical Drive, Singapore, 117456 Singapore.
authors.forename: Willie
authors.initials: W
authors.lastname: Yu
authors.affiliation: Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610 Singapore ; Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857 Singapore.
authors.forename: Hong Lee
authors.initials: HL
authors.lastname: Heng
authors.affiliation: Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610 Singapore ; Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857 Singapore.
authors.forename: Anna
authors.initials: A
authors.lastname: Gan
authors.affiliation: Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610 Singapore ; Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857 Singapore.
authors.forename: Swe Swe
authors.initials: SS
authors.lastname: Myint
authors.affiliation: Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610 Singapore ; Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857 Singapore.
authors.forename: Ee Yan
authors.initials: EY
authors.lastname: Siew
authors.affiliation: Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610 Singapore ; Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857 Singapore ; National University of Singapore, Graduate School for Integrative Sciences and Engineering, 28 Medical Drive, Singapore, 117456 Singapore.
authors.forename: Lian Dee
authors.initials: LD
authors.lastname: Ler
authors.affiliation: Department of Urology, Singapore General Hospital, Outram Road, Singapore, 169608 Singapore.
authors.forename: Lay Guat
authors.initials: LG
authors.lastname: Ng
authors.affiliation: Department of Chemical Engineering and Biotechnology, Graduate Institute of Biotechnology, National Taipei University of Technology, 1, Section 3, Chung-hsiao East Road, Taipei, 10608 Taiwan.
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Weng
authors.affiliation: Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, Linkou, School of Medicine, Chang Gung University, 5, Fusing Street, Gueishan Township, Taoyuan County 333 Taiwan.
authors.forename: Cheng-Keng
authors.initials: CK
authors.lastname: Chuang
authors.affiliation: Department of Urology, Singapore General Hospital, Outram Road, Singapore, 169608 Singapore.
authors.forename: John Sp
authors.initials: JS
authors.lastname: Yuen
authors.affiliation: Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, Linkou, School of Medicine, Chang Gung University, 5, Fusing Street, Gueishan Township, Taoyuan County 333 Taiwan.
authors.forename: See-Tong
authors.initials: ST
authors.lastname: Pang
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857 Singapore ; Division of Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610 Singapore ; Cancer Science Institute of Singapore, National University of Singapore, Centre for Life Sciences, 28 Medical Drive, Singapore, 117456 Singapore ; Genome Institute of Singapore, 60 Biopolis Street Genome, Singapore, 138672 Singapore.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.affiliation: Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610 Singapore ; Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857 Singapore ; Cancer Science Institute of Singapore, National University of Singapore, Centre for Life Sciences, 28 Medical Drive, Singapore, 117456 Singapore.
authors.forename: Bin Tean
authors.initials: BT
authors.lastname: Teh
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857 Singapore ; Centre for Computational Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857 Singapore.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Rozen