DNA sequencing of 9 Taiwanese patients with upper-urinary tract urothelial cell carcinoma who are suspected of exposure to aristolochic acid

Aristolochic acid (AA), a natural product of Aristolochia plants found in herbal remedies and health supplements, is a Group 1 carcinogen that can cause nephrotoxicity and upper urinary tract urothelial cell carcinoma (UTUC). Whole genome and exome analysis of 9 AA-associated UTUCs revealed a strikingly high somatic mutation rate (150 mutations/Mb), exceeding smoking-associated lung cancer (8 mutations/Mb) and ultraviolet radiation-associated melanoma (111 mutations/Mb). The AA-UTUC mutational signature was characterized by A:T to T:A transversions at the sequence motif A[C|T]AGG, located primarily on non-transcribed strands. AA-induced mutations were also significantly enriched at splice sites, suggesting a role for splice site mutations in UTUC pathogenesis.