Analysis of TP53 mutation spectra reveals the fingerprint of the potent environmental carcinogen, aristolochic acid

Abstract

Genetic alterations in cancer tissues may reflect the mutational fingerprint of environmental carcinogens. Here we review the pieces of evidence that support the role of aristolochic acid (AA) in inducing a mutational fingerprint in the tumor suppressor gene TP53 in urothelial carcinomas of the upper urinary tract (UUT). Exposure to AA, a nitrophenathrene carboxylic acid present in certain herbal remedies and in flour prepared from wheat grain contaminated with seeds of Aristolochia clematitis, has been linked to chronic nephropathy and UUT. TP53 mutations in UUT of individuals exposed to AA reveal a unique pattern of mutations characterized by A to T transversions on the non-transcribed strand, which cluster at hotspots rarely mutated in other cancers. This unusual pattern, originally discovered in UUTs from two different populations, one in Taiwan, and one in the Balkans, has been reproduced experimentally by treating mouse cells that harbor human TP53 sequences with AA. The convergence of molecular epidemiological and experimental data establishes a clear causal association between exposure to the human carcinogen AA and UUT. Despite bans on the sale of herbs containing AA, their use continues, raising global public health concern and an urgent need to identify populations at risk.

Keywords: 7-(deoxyadenosin-N(6)-yl)aristolactam; AA; AA-UUT; AL-DNA adducts; AL-dA; Aristolochic acid(s); BEN; Balkan endemic nephropathy; COSMIC; Catalogue of Somatic Mutations in Cancer; HUF; Herbal remedies; Hotspot mutations; Hupki embryonic fibroblasts; IARC; IARC DB; IARC TP53 Database; ICGC; International Agency for Research on Cancer; International Cancer Genome Consortium; LOF; Nephropathy; TP53; TP53 mutation; Trp53; UUT; UUT tumors from patient cohorts with documented or suspected exposure to AA; UUT tumors from patient cohorts with no known or suspected exposure to AA; Urothelial cancer; aristolactam-DNA adducts; loss of wild-type function; nonAA-UUT; the human p53 tumor suppressor gene; the mouse p53 tumor suppressor gene; upper urinary tract tumors.