Aristolochic Acid in the Etiology of Renal Cell Carcinoma

Abstract

Background 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). Methods 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. Results 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. Conclusions This study strongly suggests that AA contributes to the etiology of certain RCCs. Impact 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.

Herbal medicine containing aristolochic acid and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection

“…12,13 Finally, aristolactam-DNA adducts were also detected in 76% of clear cell renal cell carcinoma (ccRCC) and AA-mutational signature was evident in 6 of 10 sequenced ccRCC exomes from Taiwanese patients. 14 Aristolochic acid treatment in rat resulted in DNA adduct formation, and increased mutant frequency in the liver as well as kidneys. 15 It was suspected that aristolochic acidinduced mutations in concert with hepatitis B virus (HBV) play an important role in liver carcinogenesis.…”

“…investigated 152 patients with upper urinary tract urothelial carcinoma and found the 93 had been exposed to aristolochic acid based on the presence of aristolactam‐DNA adducts and AA‐mutational signature in the renal cortex . Finally, aristolactam‐DNA adducts were also detected in 76% of clear cell renal cell carcinoma (ccRCC) and AA‐mutational signature was evident in 6 of 10 sequenced ccRCC exomes from Taiwanese patients …”

DNA adducts: Formation, biological effects, and new biospecimens for mass spectrometric measurements in humans

“…Since most DNA adducts can lead to many types of mutations, the establishment of a direct link between a specific DNA adduct and the induction of a mutation is tenuous in humans. However, AFB 1 and AA are two examples where environmental exposures have been definitively linked to signature mutations and the development of cancer in humans . AFB 1 , is a fungal toxicant and a potent animal liver carcinogen that is found as a contaminant in various crops .…”

Bioactivation mechanisms of N‐hydroxyaristolactams: Nitroreduction metabolites of aristolochic acids

“…Therefore, toxicities of AA in humans have long been overlooked. Recently, owing to the advances in mass spectrometry and next generation sequencing techniques, AA ingestion has been implicated in the etiology of renal cell carcinoma (Scelo et al 2014;Jelakovic et al 2015;Hoang et al 2016;Turesky et al 2016), bladder cancer (Poon et al 2015), intrahepatic cholangiocarcinoma (Zou et al 2014), and hepatocellular carcinoma (Poon et al 2013;Totoki et al 2014;Ng et al 2017). These findings indicate that exposure to AA contributes significantly to kidney disease and cancer worldwide.…”