Aristolochic acids and their derivatives are widely implicated in liver cancers in Taiwan and throughout Asia

Abstract

Many traditional pharmacopeias include and related plants, which contain nephrotoxins and mutagens in the form of aristolochic acids and similar compounds (collectively, AA). AA is implicated in multiple cancer types, sometimes with very high mutational burdens, especially in upper tract urothelial cancers (UTUCs). AA-associated kidney failure and UTUCs are prevalent in Taiwan, but AA's role in hepatocellular carcinomas (HCCs) there remains unexplored. Therefore, we sequenced the whole exomes of 98 HCCs from two hospitals in Taiwan and found that 78% showed the distinctive mutational signature of AA exposure, accounting for most of the nonsilent mutations in known cancer driver genes. We then searched for the AA signature in 1400 HCCs from diverse geographic regions. Consistent with exposure through known herbal medicines, 47% of Chinese HCCs showed the signature, albeit with lower mutation loads than in Taiwan. In addition, 29% of HCCs from Southeast Asia showed the signature. The AA signature was also detected in 13 and 2.7% of HCCs from Korea and Japan as well as in 4.8 and 1.7% of HCCs from North America and Europe, respectively, excluding one U.S. hospital where 22% of 87 "Asian" HCCs had the signature. Thus, AA exposure is geographically widespread. Asia, especially Taiwan, appears to be much more extensively affected, which is consistent with other evidence of patterns of AA exposure. We propose that additional measures aimed at primary prevention through avoidance of AA exposure and investigation of possible approaches to secondary prevention are warranted.

Recognition of the toxicity of aristolochic acid

“…The results showed that 78% (76/98) of HCCs had the unique mutational signature of AA exposure. The researchers then screened for the AA signature in 1400 HCCs from diverse geographic regions and detected it in 47% (42/89) of the samples from mainland China, 29% (10/35) of the samples from Southeast Asia, 13% (29/231) of the samples from Korea, 2.7% (13/477) of the samples from Japan, 4.8% (10/209) of the samples from North America and 1.7% (4/230) of the samples from Europe . Collectively, these data indicate that the AA signature is closely associated with HCCs in Asia.…”

“…Aristolochia manshuriensis in Long Dan Xie Gan Wan was replaced with Caulis Akebiae in the 2005 Pharmacopoeia of PR China . Since 2003, some AA‐containing herbal remedies have been officially prohibited in Taiwan, and AA‐containing herbs were withdrawn from the market by the local health authority of Hong Kong in June 2004 …”

The Mutational Features of Aristolochic Acid–Induced Mouse and Human Liver Cancers

“…In 2012, we found that the characteristic A>T transversions were significantly enriched in 4 of 10 hepatitis B virus–associated hepatocellular carcinoma (HCC) specimens from China, indicating the possibility of AA exposure. In 2017, a survey on a larger cohort of HCC patients indicated that the AA mutational signature was widely found in Asian HCC patients, especially those from Taiwan …”

Assessment of Pig‐a, Micronucleus, and Comet Assay Endpoints in Tg.RasH2 Mice Carcinogenicity Study of Aristolochic Acid I

“…Epidemiology studies have shown that AAI is implicated in multiple cancer types, including upper tract urothelial cancers and HBV-related liver cancers Ng et al 2017). Epidemiology studies have shown that AAI is implicated in multiple cancer types, including upper tract urothelial cancers and HBV-related liver cancers Ng et al 2017).…”