Benzo[a]pyrene-induced murine skin tumors exhibit frequent and characteristic G to T mutations in the p53 gene.
Human tobacco-related cancers exhibit a high frequency of G to T transversions in the mutation hot spot region of the p53 tumor suppressor gene, possibly the result of specific mutagens in tobacco smoke, most notably benzo[a]pyrene (B[a]P). No in vivo animal model of B[a]P-induced tumorigenesis has been used, however, to substantiate these molecular epidemiological data experimentally. Direct DNA sequence analysis of the hot spot region (exons 5-8 inclusive) of murine p53 was performed in 20 skin tumors induced by a complete carcinogenesis protocol with B[a]P. Sequence analyses revealed numerous heterozygous missense mutations in carcinomas, specifically in exons 7 and 8 of the p53 gene, and targeting exclusively guanine residues. Moreover, 70% (5/7) of the mutations characterized were G to T transversions. In contrast, direct DNA sequence analysis of 36 skin tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) in either a complete carcinogenesis protocol or in a two-stage carcinogenesis protocol revealed a 30% frequency of heterozygous p53 mutations, with the majority of mutations found in carcinomas, but only a single G to T transversion (1/8). Thus, while mutation frequencies are similar, the pattern and type of p53 mutations in B[a]P-induced skin tumors differs significantly from the mutation spectra in DMBA-induced squamous neoplasias. These in vivo findings in B[a]P-induced tumors lend support to in vitro and molecular epidemiological evidence, suggesting that the p53 tumor suppressor gene may be a selective target of metabolically activated B[a]P species etiologically associated with human tobacco-related cancers.
Ruggeri
B
B
Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA 19111.
DiRado
M
M
Zhang
S Y
SY
Bauer
B
B
Goodrow
T
T
Klein-Szanto
A J
AJ
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000818:Animals; D001564:Benzo(a)pyrene / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology; D016147:Genes, Tumor Suppressor / Q000235:genetics*; D006579:Heterozygote; D007150:Immunohistochemistry; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics*; D010212:Papilloma / Q000235:genetics / Q000473:pathology; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D016159:Tumor Suppressor Protein p53; D001564:Benzo(a)pyrene; D015127:9,10-Dimethyl-1,2-benzanthracene