Aristolochic Acid in the Etiology of Renal Cell Carcinoma

Margaret L. Hoang, Chung-Hsin Chen, Pau-Chung Chen, Nicholas J. Roberts, Kathleen G. Dickman, Byeong Hwa Yun, Robert J. Turesky, Yeong-Shiau Pu, Bert Vogelstein, Nickolas Papadopoulos, Arthur P. Grollman, Kenneth W. Kinzler, Thomas A. Rosenquist

Aristolochia species used in the practice of traditional herbal medicine contain 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. We here investigated whether AA is also an etiologic factor in clear cell renal cell carcinoma (ccRCC). 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 ten Taiwanese ccRCC pateints with prior exposure to AA were determined. Cumulative ingestion of more than 250 milligrams of AA increased risk of ccRCC (OR 1.25) and we detected dA-AL-I adducts in 76% of Taiwanese ccRCC patients. Further, the distinctive AA-mutational signature was evident in six of ten sequenced ccRCC exomes from Taiwanese patients. This study strongly suggests that AA contributes to the etiology of certain renal cell carcinomas. The present study offers compelling evidence implicating AA in a significant fraction of the RCC arising in Taiwan and illustrates the power of integrating epidemiological, molecular and genetic data in the investigation of cancer etiology.