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

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 uppe...

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Bibliographic Details
Published in:Mutation research. Reviews in mutation research 2013-07, Vol.753 (1), p.41-49
Main Authors: Hollstein, M., Moriya, M., Grollman, A.P., Olivier, M.
Format: Article
Language:English
Subjects:
Aristolochic acid(s)
Biological and medical sciences
Cell physiology
Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes
Fundamental and applied biological sciences. Psychology
Herbal remedies
Hotspot mutations
Medical sciences
Molecular and cellular biology
Molecular genetics
Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
Mutagenesis. Repair
Nephropathy
TP53 mutation
Tumors
Urothelial cancer
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Summary: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.
ISSN:1383-5742
1388-2139
DOI:10.1016/j.mrrev.2013.02.003