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Review
. 2013 Jul-Sep;753(1):41-49.
doi: 10.1016/j.mrrev.2013.02.003. Epub 2013 Feb 17.

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

M Hollstein  1 , M Moriya  2 , A P Grollman  2 , M Olivier  3
Affiliations
Review

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

M Hollstein et al. Mutat Res. 2013 Jul-Sep.

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.

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Figures

Figure 1
Figure 1
Aristolochia littoralis and structures of aristolochic acids.
Figure 2
Figure 2
Codon distribution of A:T>T:A substitutions in TP53 coding sequence in (A) AA-UUT cancers [17;19;21;39], and in (B) other cancer types (IARC TP53 Database, R15, excluding AA-related cancers and cell-lines). Codon labels are shown for mutations representing more than 2% of all coding mutations. Note that intronic mutations located at splice sites (first and last nucleotides of introns) are not depicted in this chart.
Figure 2
Figure 2
Codon distribution of A:T>T:A substitutions in TP53 coding sequence in (A) AA-UUT cancers [17;19;21;39], and in (B) other cancer types (IARC TP53 Database, R15, excluding AA-related cancers and cell-lines). Codon labels are shown for mutations representing more than 2% of all coding mutations. Note that intronic mutations located at splice sites (first and last nucleotides of introns) are not depicted in this chart.
Figure 3
Figure 3
Sequence context of A>T mutations in AA-UUT cancers. Motif surrounding the A nucleotide involved in the A>T mutations associated with AA exposure in UUT, taking into account (A) all A>T mutations, or (B) only A>T resulting in missense or nonsense mutations.
Figure 4
Figure 4
Overlap in identity of specific A to T mutations in AA-UUT and in AA HUFs. Left panel: Overlap between the specific A:T>T:A AA-associated mutations in Hupki (N=18 unique mutations) and in AA-UUT (N=46 unique mutations). Right panel: details on the specific mutations overlapping between Hupki and human data. Mutations are described using NCBI reference sequence NM_000546 for cDNA description and NP_000537 for protein description.
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