Aristolochic acid-induced upper tract urothelial carcinoma in Taiwan: Clinical characteristics and outcomes
Journal
International Journal of Cancer
Journal Volume
133
Journal Issue
1
Pages
14-20
Date Issued
2013
Author(s)
Dickman K.G.
Moriya M.
Tai H.-C.
Grollman A.P.
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. What's new? Aristolochic acid, a component of all Aristolochia-based herbal medicines, is a potent nephrotoxin and human carcinogen associated with upper urinary tract urothelial carcinoma (UUC). This is the first clinical study to characterize aristolochic acid-induced UUC using two newly developed biomarkers, aristolactam-DNA adducts in renal cortex and a signature TP53 mutation. Aristolochic acid-induced UUC patients tended to be younger than other UUC patients and predominantly female and had more advanced renal disease. AA exposure was associated with an increased risk for developing synchronous bilateral and metachronous contralateral UUC. This pattern distinguishes AA from other carcinogens involved in the etiology of UUC. Copyright ? 2013 UICC.
SDGs
Other Subjects
adenosine; aristolochic acid; cytidine; protein p53; uracil; adult; age distribution; aged; article; bladder cancer; cancer recurrence; cancer risk; cancer survival; carcinogen testing; clinical article; controlled study; DNA adduct; female; gene sequence; human; kidney cortex; male; mutational analysis; nephrotoxicity; nucleic acid base substitution; outcome assessment; priority journal; sex difference; smoking; Taiwan; tp53 gene; transitional cell carcinoma; Adenine; Adult; Age Factors; Aged; Aged, 80 and over; Aristolochic Acids; Carcinogens; Carcinoma, Transitional Cell; DNA Adducts; DNA, Neoplasm; Drugs, Chinese Herbal; Female; Heterocyclic Compounds with 4 or More Rings; Humans; Kaplan-Meier Estimate; Kidney Failure, Chronic; Male; Middle Aged; Mutagens; Mutation; Neoplasms, Multiple Primary; Neoplasms, Second Primary; Recurrence; Risk Factors; Sequence Analysis, DNA; Sex Factors; Taiwan; Transcriptome; Treatment Outcome; Tumor Suppressor Protein p53; Urologic Neoplasms
Type
journal article