Benzo[a]pyrene, aflatoxine B₁ and acetaldehyde mutational patterns in TP53 gene using a functional assay: relevance to human cancer aetiology.
Mutations in the TP53 gene are the most common alterations in human tumours. TP53 mutational patterns have sometimes been linked to carcinogen exposure. In hepatocellular carcinoma, a specific G>T transversion on codon 249 is classically described as a fingerprint of aflatoxin B(1) exposure. Likewise G>T transversions in codons 157 and 158 have been related to tobacco exposure in human lung cancers. However, controversies remain about the interpretation of TP53 mutational pattern in tumours as the fingerprint of genotoxin exposure. By using a functional assay, the Functional Analysis of Separated Alleles in Yeast (FASAY), the present study depicts the mutational pattern of TP53 in normal human fibroblasts after in vitro exposure to well-known carcinogens: benzo[a]pyrene, aflatoxin B(1) and acetaldehyde. These in vitro patterns of mutations were then compared to those found in human tumours by using the IARC database of TP53 mutations. The results show that the TP53 mutational patterns found in human tumours can be only partly ascribed to genotoxin exposure. A complex interplay between the functional impact of the mutations on p53 phenotype and the cancer natural history may affect these patterns. However, our results strongly support that genotoxins exposure plays a major role in the aetiology of the considered cancers.
Groupe Régional d'Etudes sur le Cancer-EA 1772, Université de Caen Basse-Normandie, Caen, France.
Vincent
V
Paget
Mathilde
M
Lechevrel
Véronique
V
André
Jérémie Le
JL
Goff
Didier
D
Pottier
Sylvain
S
Billet
Guillaume
G
Garçon
Pirouz
P
Shirali
François
F
Sichel
D000079:Acetaldehyde / Q000633:toxicity; D016604:Aflatoxin B1 / Q000633:toxicity; D001564:Benzo(a)pyrene / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity*; D005347:Fibroblasts; D006801:Humans; D009153:Mutagens; D009154:Mutation; D009369:Neoplasms / Q000139:chemically induced / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D002273:Carcinogens; D009153:Mutagens; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D001564:Benzo(a)pyrene; D016604:Aflatoxin B1; D000079:Acetaldehyde