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

Abstract

Background: The purpose of this study was to investigate the cancer incidence in patients with end-stage aristolochic acid nephropathy (AAN). Methods: A total of 102 patients with end-stage AAN treated in our hospital between 2004 and 2013 were included in this study. The correlation of cancer incidence with age, gender, dosage of aristolochic acid (AA), the type of renal replacement therapies, and the polymorphisms of quinone oxidoreductase 1 (NQO1) C609T and cytochrome P450 1A1 (CYP1A1) A4889G was examined. Results: The cancer incidence rate in our patients was 41.2% (42 in 102) including 39 cases of urinary cancer. The mortality rate in the patients with cancer was significantly higher than that in the patients without cancer (31%, 13/42 vs. 11.7%, 7/60, p50.05). Thirteen patients developed cancer before entering end-stage renal disease (ESRD). Cancer incidence was significantly associated with the dosage of AA consumption (p ¼ 0.091). Hemodialysis, peritoneal dialysis and renal transplant did not affect the cancer incidence in our patients differently, but appeared to be associated with cancer at particular locations of urinary system. The patients undergoing hemodialysis seemed to more likely have bladder cancer (72.72%), while the patients receiving peritoneal dialysis appeared to develop cancer predominantly in the upper urinary tract (66.67%). Conclusions: The cancer initiation in our patients seems significantly correlate with the dosage of AA consumption. Different renal replacement therapies appear to be associated with cancer at particular locations of urinary system in our patients.

Recognition of the toxicity of aristolochic acid

“…AL-DNA adducts persist in the renal cortex for many years and thus serves powerful biomarkers of AA exposure. 17 A previous study detected a A:T-to-T:A mutation in codon 139 (Lys-Stop) of exon 5 in the p53 gene in DNA isolated from an AAN-associated urothelial carcinoma. 18…”

“…In addition, AA destroys DNA by forming covalent aristolactam (AL)‐DNA adducts after the metabolic activation of AA, resulting in loss‐of‐function mutations in the tumour‐suppressor gene TP53 and functional mutations in the oncogenes FGFR3 and H‐RAS. AL‐DNA adducts persist in the renal cortex for many years and thus serves powerful biomarkers of AA exposure . A previous study detected a A:T‐to‐T:A mutation in codon 139 (Lys‐Stop) of exon 5 in the p53 gene in DNA isolated from an AAN‐associated urothelial carcinoma .…”

Systematic Overview of Aristolochic Acids: Nephrotoxicity, Carcinogenicity, and Underlying Mechanisms

“…In 2002 and 2012, the World Health Organization International Agency for Research on Cancer (IARC) classified AAs as group I carcinogen according to the available strong evidence that AA-specific DNA adducts and TP53 mutations were found in humans exposed to materials obtained from plant species containing AAs (IARC, 2002; IARC, 2012). However, despite a high mutagenic and carcinogenic potential, herbal remedies and products containing AAs are still used in Asia contributing to a high incidence of urothelial carcinoma (Chen et al, 2012; Yang et al, 2014; Sun et al, 2015).…”

“…Usually, these tumors have a high mortality rate. The urothelial carcinomas are mainly of synchronous bilateral or metachronous contralateral type and are related to the cumulative exposure of AAs (Chen et al, 2013; Sun et al, 2015). In addition, AA-derived DNA adducts and TP53 mutations are clinically meaningful to explore the involvement of AAs in UTUC (Chen et al, 2012; Chen et al, 2013; Aydin et al, 2014; Yang et al, 2014; Sun et al, 2015).…”

“…Recently, a specific mutational signature of AA exposure has been exhibited in whole exome sequencing of hepatocellular carcinomas, suggesting a plausible conclusion that AAs and their derivatives might be one of the culprits triggering liver cancer in Asia (Totoki et al, 2014; Letouze et al, 2017; Ng et al, 2017; Nault and Letouze, 2019). AAs can also affect the initiation and/or progression of renal cell carcinoma (Scelo et al, 2014; Jelakovic et al, 2015a; Hoang et al, 2016) or bladder urothelial tumor (Lemy et al, 2008; Poon et al, 2015; Sun et al, 2015).…”