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Aristolochic Acid in the Etiology of Renal Cell Carcinoma
Margaret L Hoang1, Chung-Hsin Chen2, Pau-Chung Chen3
1Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland.
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. Cancer Epidemiol Biomarkers Prev; 25(12); 1600-8. ©2016 AACR.
Insights
Aristolochic acid (AA), a carcinogen found in traditional herbal medicines, is linked to an increased risk of clear cell renal cell carcinoma (ccRCC). This study found AA DNA adducts and mutational signatures in Taiwanese ccRCC patients, supporting its role in kidney cancer development.
Area of Science:
- Oncology
- Toxicology
- Genetics
Background:
- Aristolochic acid (AA) from Aristolochia species is a known human carcinogen linked to urothelial carcinomas.
- AA forms DNA adducts, specifically aristolactam (AL)-DNA adducts, in genomic DNA.
- The potential role of AA in the etiology of clear cell renal cell carcinoma (ccRCC) was investigated.
Purpose of the Study:
- To determine if aristolochic acid (AA) is an etiologic factor in clear cell renal cell carcinoma (ccRCC).
- To investigate the association between Aristolochia exposure, AA consumption, and ccRCC incidence.
- To identify AA-DNA adducts and mutational signatures in ccRCC tumors.
Main Methods:
- A population-based case-control study in Taiwan involving 5,709 ccRCC cases and 22,836 controls.
- Analysis of dA-AL-I adducts in kidney DNA from 51 Taiwanese ccRCC patients.
- Whole-exome sequencing of ccRCC tumors from 10 Taiwanese patients with prior AA exposure.
Main Results:
- Cumulative AA ingestion >250 mg was associated with increased ccRCC risk (OR, 1.25).
- dA-AL-I adducts were detected in 76% of Taiwanese ccRCC patients.
- A distinctive AA mutational signature was found in six of 10 sequenced ccRCC exomes.
Conclusions:
- The study provides strong evidence that AA contributes to the etiology of certain renal cell carcinomas (RCCs).
- AA is implicated in a significant proportion of RCC cases in Taiwan.
- Integrating epidemiologic, molecular, and genetic data is crucial for understanding cancer etiology.
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