title: Mutational signature of aristolochic acid: Clue to the recognition of a global disease.
abstract: Mutational signatures associated with specific forms of DNA damage have been identified in several forms of human cancer. Such signatures provide information regarding mechanisms of tumor induction which, in turn, can reduce exposure to carcinogens by shaping public health policy. Using a molecular epidemiologic approach that takes advantage of recent advances in genome sequencing while applying sensitive and specific analytical methods to characterize DNA damage, it has become increasingly possible to establish causative linkages between certain environmental mutagens and disease risk. In this perspective, we use aristolochic acid, a human carcinogen and nephrotoxin found in Aristolochia herbs, to illustrate the power and effectiveness of this multidisciplinary approach. The genome-wide mutational signature for this toxin, detected initially in cancers of the upper urinary tract, has subsequently been associated with cancers of the liver and kidney. These findings have significant implications for global public health, especially in China, where millions of individuals have used Aristolochia herbal remedies as part of traditional Chinese medicine and, thus, are at risk of developing aristolochic acid nephropathy and/or upper urinary tract carcinomas. The studies reported here set the stage for research into prevention and early detection, both of which will be required to manage a potentially devastating global disease.
authors.affiliation: Stony Brook University School of Medicine, Department of Pharmacological Sciences, Laboratory of Chemical Biology, Stony Brook, NY, 11794, United States.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Rosenquist
authors.affiliation: Stony Brook University School of Medicine, Department of Pharmacological Sciences, Laboratory of Chemical Biology, Stony Brook, NY, 11794, United States. Electronic address: apg@pharm.stonybrook.edu.
authors.forename: Arthur P
authors.initials: AP
authors.lastname: Grollman
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity*; D030022:Aristolochia / Q000737:chemistry / Q000633:toxicity; D034341:Aristolochic Acids / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002277:Carcinoma / Q000139:chemically induced / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D018736:DNA Adducts / Q000819:agonists / Q000096:biosynthesis; D004249:DNA Damage; D004260:DNA Repair; D020022:Genetic Predisposition to Disease; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014571:Urologic Neoplasms / Q000139:chemically induced / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*
chemical_list: D000477:Alkylating Agents; D034341:Aristolochic Acids; D002273:Carcinogens; D018736:DNA Adducts
keywords: Aristolochia; Aristolochic acid; DNA repair; Endemic nephropathy; Environmental mutagen; Mutational signature; Upper urinary tract carcinoma