title: Aristolochic Acid in the Etiology of Renal Cell Carcinoma.
abstract: Aristolochia species used in the practice of traditional herbal medicine contains aristolochic acid (AA), an established human carcinogen contributing to urothelial carcinomas of the upper urinary tract. AA binds covalently to genomic DNA, forming aristolactam (AL)-DNA adducts. Here we investigated whether AA is also an etiologic factor in clear cell renal cell carcinoma (ccRCC).
  
  
  
  We conducted a population-based case-control study to investigate the linkage between Aristolochia prescription history, cumulative AA consumption, and ccRCC incidence in Taiwan (5,709 cases and 22,836 matched controls). The presence and level of mutagenic dA-AL-I adducts were determined in the kidney DNA of 51 Taiwanese ccRCC patients. The whole-exome sequences of ccRCC tumors from 10 Taiwanese ccRCC patients with prior exposure to AA were determined.
  
  
  
  Cumulative ingestion of more than 250 mg of AA increased risk of ccRCC (OR, 1.25), and we detected dA-AL-I adducts in 76% of Taiwanese ccRCC patients. Furthermore, the distinctive AA mutational signature was evident in six of 10 sequenced ccRCC exomes from Taiwanese patients.
  
  
  
  This study strongly suggests that AA contributes to the etiology of certain RCCs.
  
  
  
  The current study offers compelling evidence implicating AA in a significant fraction of the RCC arising in Taiwan and illustrates the power of integrating epidemiologic, molecular, and genetic data in the investigation of cancer etiology. Cancer Epidemiol Biomarkers Prev; 25(12); 1600-8. ©2016 AACR.
authors.affiliation: Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland.
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Hoang
authors.affiliation: Department of Urology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.
authors.forename: Chung-Hsin
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Occupational and Environmental Medicine, National Taiwan University Hospital and Institute of Occupational Medicine and Industrial Hygiene, National Taiwan University, Taipei, Taiwan.
authors.forename: Pau-Chung
authors.initials: PC
authors.lastname: Chen
authors.affiliation: Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Roberts
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York.|Department of Medicine, Stony Brook University, Stony Brook, New York.
authors.forename: Kathleen G
authors.initials: KG
authors.lastname: Dickman
authors.affiliation: Masonic Cancer Center and Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Byeong Hwa
authors.initials: BH
authors.lastname: Yun
authors.affiliation: Masonic Cancer Center and Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Turesky
authors.affiliation: Department of Urology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.
authors.forename: Yeong-Shiau
authors.initials: YS
authors.lastname: Pu
authors.affiliation: Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland.
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.affiliation: Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland.
authors.forename: Nickolas
authors.initials: N
authors.lastname: Papadopoulos
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York.|Department of Medicine, Stony Brook University, Stony Brook, New York.
authors.forename: Arthur P
authors.initials: AP
authors.lastname: Grollman
authors.affiliation: Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland. Thomas.rosenquist@stonybrook.edu kinzlke@jhmi.edu.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York. Thomas.rosenquist@stonybrook.edu kinzlke@jhmi.edu.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Rosenquist
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D034341:Aristolochic Acids / Q000032:analysis / Q000494:pharmacology / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity; D002292:Carcinoma, Renal Cell / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics; D016022:Case-Control Studies; D004247:DNA / Q000187:drug effects; D018736:DNA Adducts / Q000032:analysis*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009153:Mutagens / Q000633:toxicity; D009154:Mutation; D013624:Taiwan / Q000453:epidemiology
chemical_list: D034341:Aristolochic Acids; D002273:Carcinogens; D018736:DNA Adducts; D009153:Mutagens; D004247:DNA; C000228:aristolochic acid I