Background: Aristolochia species used in the practice of traditional herbal medicine contains aristolochic acid (AA), an establishedhuman 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.
Bibliographical noteFunding Information:
This research was supported, in part, by Taiwan National Science Council grants 101-2314-B-002-027-MY3 (to C.H. Chen) and 101-2314-B-002-023- MY3 (to Y.S. Pu). Additional support included the Virginia and D.K. Ludwig Fund for Cancer Research, Commonwealth Foundation, and NIH grants CA057345 (to K.W. Kinzler), CA190889 (to N.J. Roberts), and ES019564 (to R.J. Turesky), HHMI (to B.V. Vogelstein), and Marsha and Henry Laufer (to A.P. Grollman). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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