title: Aristolochic acid-induced upper tract urothelial carcinoma in Taiwan: clinical characteristics and outcomes.
abstract: Aristolochic acid (AA), a component of all Aristolochia-based herbal medicines, is a potent nephrotoxin and human carcinogen associated with upper urinary tract urothelial carcinoma (UUC). To investigate the clinical and pathological characteristics of AA-induced UUC, this study included 152 UUC patients, 93 of whom had been exposed to AA based on the presence of aristolactam-DNA adducts in the renal cortex. Gene sequencing was used to identify tumors with A:T-to-T:A transversions in TP53, a mutational signature associated with AA. Cases with both aristolactam-DNA adducts and A:T-to-T:A transversions in TP53 were defined as AA-UUC, whereas patients lacking both of these biomarkers were classified as non-AA-UUC. Cases with either biomarker were classified as possible-AA-UUC. Forty (26%), 60 (40%), and 52 (34%) patients were classified as AA-UUC, possible-AA-UUC and non-AA-UUC, respectively. AA-UUC patients were younger (median ages: 64, 68, 68 years, respectively; p=0.189), predominately female (65%, 42%, 35%, respectively; p=0.011), had more end-stage renal disease (28%, 10%, 12%, respectively; p=0.055), and were infrequent smokers (5%, 22%, 33%, respectively; p=0.07) compared to possible-AA-UUC and non-AA-UUC patients. All 14 patients who developed contralateral UUC had aristolactam-DNA adducts; ten of these also had signature mutations. The contralateral UUC-free survival period was shorter in AA-UUC compared to possible- or non-AA-UUC (p=0.019 and 0.002, respectively), whereas no differences among groups were observed for bladder cancer recurrence. In conclusion, AA-UUC patients tend to be younger and female, and have more advanced renal disease. Notably, AA exposure was associated with an increased risk for developing synchronous bilateral and metachronous contralateral UUC.
authors.affiliation: Department of Urology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chung-Hsin
authors.initials: CH
authors.lastname: Chen
authors.forename: Kathleen G
authors.initials: KG
authors.lastname: Dickman
authors.forename: Chao-Yuan
authors.initials: CY
authors.lastname: Huang
authors.forename: Masaaki
authors.initials: M
authors.lastname: Moriya
authors.forename: Chia-Tung
authors.initials: CT
authors.lastname: Shun
authors.forename: Huai-Ching
authors.initials: HC
authors.lastname: Tai
authors.forename: Kuo-How
authors.initials: KH
authors.lastname: Huang
authors.forename: Shuo-Meng
authors.initials: SM
authors.lastname: Wang
authors.forename: Yuan-Ju
authors.initials: YJ
authors.lastname: Lee
authors.forename: Arthur P
authors.initials: AP
authors.lastname: Grollman
authors.forename: Yeong-Shiau
authors.initials: YS
authors.lastname: Pu
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D034341:Aristolochic Acids / Q000009:adverse effects*; D002273:Carcinogens; D002295:Carcinoma, Transitional Cell / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D018736:DNA Adducts / Q000187:drug effects / Q000378:metabolism; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D003839:Deoxyadenosines; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D007676:Kidney Failure, Chronic / Q000209:etiology; D008297:Male; D008875:Middle Aged; D009153:Mutagens / Q000009:adverse effects*; D009154:Mutation; D009378:Neoplasms, Multiple Primary / Q000139:chemically induced; D016609:Neoplasms, Second Primary / Q000139:chemically induced; D012008:Recurrence; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D012737:Sex Factors; D013624:Taiwan / Q000453:epidemiology; D059467:Transcriptome; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014571:Urologic Neoplasms / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics / Q000473:pathology
chemical_list: C405699:7-(deoxyadenosin-N(6)--yl)aristolactam II; D034341:Aristolochic Acids; D002273:Carcinogens; D018736:DNA Adducts; D004273:DNA, Neoplasm; D003839:Deoxyadenosines; D004365:Drugs, Chinese Herbal; D006576:Heterocyclic Compounds, 4 or More Rings; D009153:Mutagens; D016159:Tumor Suppressor Protein p53; C000228:aristolochic acid I; D000225:Adenine