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.

Urologic cancer in Taiwan

“…There is possible correlation between UUC and aristolochic acid (AA), a component of all aristolochia-based herbal medicines. AA exposure was associated with an increased risk for developing synchronous bilateral and metachronous contralateral UUC (30). Following metabolic activation, AA reacts with DNA to form aristolactam-DNA adducts, which then results in a unique mutation in the TP53 tumour-suppressor gene in the urothelium (31).…”

Kidney Cancer Linked to Chronic Hepatitis in the Asia-Pacific: A Population-Based Analysis

“…Associated comorbidities, such as diabetes mellitus, hypertension, hyperlipidemia, coronary artery disease (CAD), renal disease, liver cirrhosis, and organ transplantation, diagnosed or performed after 2000 were ascertained by using diagnostic codes. Aristolochic acid (AA) is a nephrotoxicant suggested to be associated with AA nephropathy (AAN) and upper urothelial tract cancer [19] . Although RCC has not been linked to AAN and AA exposure previously, some recent studies implicate the potential role of AA in RCC development [20,21] .…”

Analysis of potential risk factors for cancer incidence in patients with aristolochic acid nephropathy from Wenzhou, China

“…Chen et al 21 compared the clinical and pathological characteristics of AA-induced versus non-AAinduced upper urinary tract urothelial cancer and found that patients with AA-induced cancer had a significantly higher risk of contralateral recurrence compared with patients with non-AA-induced cancer.…”