{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:04:30Z","timestamp":1791245070571,"version":"4.1.0"},"reference-count":40,"publisher":"National Academy of Sciences","issue":"21","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,5,22]]},"abstract":"<jats:p>\n                    Aristolochic acid, a potent human carcinogen produced by\n                    <jats:italic>Aristolochia<\/jats:italic>\n                    plants, is associated with urothelial carcinoma of the upper urinary tract (UUC). Following metabolic activation, aristolochic acid reacts with DNA to form aristolactam (AL)-DNA adducts. These lesions concentrate in the renal cortex, where they serve as a sensitive and specific biomarker of exposure, and are found also in the urothelium, where they give rise to a unique mutational signature in the\n                    <jats:italic>TP53<\/jats:italic>\n                    tumor-suppressor gene. Using AL-DNA adducts and\n                    <jats:italic>TP53<\/jats:italic>\n                    mutation spectra as biomarkers, we conducted a molecular epidemiologic study of UUC in Taiwan, where the incidence of UUC is the highest reported anywhere in the world and where\n                    <jats:italic>Aristolochia<\/jats:italic>\n                    herbal remedies have been used extensively for many years. Our study involves 151 UUC patients, with 25 patients with renal cell carcinomas serving as a control group. The\n                    <jats:italic>TP53<\/jats:italic>\n                    mutational signature in patients with UUC, dominated by otherwise rare A:T to T:A transversions, is identical to that observed in UUC associated with Balkan endemic nephropathy, an environmental disease. Prominent\n                    <jats:italic>TP53<\/jats:italic>\n                    mutational hotspots include the adenine bases of\n                    <jats:sup>5\u2032<\/jats:sup>\n                    AG (acceptor) splice sites located almost exclusively on the nontranscribed strand. A:T to T:A mutations also were detected at activating positions in the\n                    <jats:italic>FGFR3<\/jats:italic>\n                    and\n                    <jats:italic>HRAS<\/jats:italic>\n                    oncogenes. AL-DNA adducts were present in the renal cortex of 83% of patients with A:T to T:A mutations in\n                    <jats:italic>TP53<\/jats:italic>\n                    ,\n                    <jats:italic>FGFR3<\/jats:italic>\n                    , or\n                    <jats:italic>HRAS<\/jats:italic>\n                    . We conclude that exposure to aristolochic acid contributes significantly to the incidence of UUC in Taiwan, a finding with significant implications for global public health.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1119920109","type":"journal-article","created":{"date-parts":[[2012,4,9]],"date-time":"2012-04-09T21:05:20Z","timestamp":1334005520000},"page":"8241-8246","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":362,"title":["Aristolochic acid-associated urothelial cancer in Taiwan"],"prefix":"10.1073","volume":"109","author":[{"given":"Chung-Hsin","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Urology, National Taiwan University Hospital, Taipei, Taiwan 10002;"},{"name":"Division of Urology, Department of Health, Taoyuan General Hospital, Taoyuan, Taiwan 33004;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen G.","family":"Dickman","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences and"},{"name":"Department of Medicine, Stony Brook University, Stony Brook, NY 11794;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaaki","family":"Moriya","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiri","family":"Zavadil","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cancer Institute and Center for Health Informatics and Bioinformatics, New York University Langone Medical Center, New York, NY 10016;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktoriya S.","family":"Sidorenko","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen L.","family":"Edwards","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Institute for Public Health Genetics, University of Washington, Seattle, WA 98115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitri V.","family":"Gnatenko","sequence":"additional","affiliation":[{"name":"Department of Medicine, Stony Brook University, Stony Brook, NY 11794;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Wu","sequence":"additional","affiliation":[{"name":"Roche Molecular Systems, Pleasanton, CA 94588;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Turesky","sequence":"additional","affiliation":[{"name":"Division of Environmental Health Sciences, Wadsworth Center, New York State Department of Health, Albany, NY 12201; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue-Ru","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Urology and"},{"name":"Department of Pathology, New York University School of Medicine and Veterans Affairs Medical Center, New York, NY, 10010"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeong-Shiau","family":"Pu","sequence":"additional","affiliation":[{"name":"Department of Urology, National Taiwan University Hospital, Taipei, Taiwan 10002;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur P.","family":"Grollman","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences and"},{"name":"Department of Medicine, Stony Brook University, Stony Brook, NY 11794;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2012,4,9]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1872-0854(09)00007-1"},{"key":"e_1_3_3_2_2","first-page":"588","volume-title":"Clinical Nephrotoxins","author":"Vanherweghem JL","year":"2003","unstructured":"JL Vanherweghem, F Debelle, MC Muniz-Martinez, JL Nortier, Aristolochic acid nephropathy after Chinese herb remedies. 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