On the origin of p53 G:C --> T:A transversions in lung cancers.
The high frequency of G-->T transversions in the p53 gene is a distinctive feature of lung cancer patients with a smoking history and is commonly believed to reflect the direct mutagenic signature of polycyclic aromatic hydrocarbon (PAH) adducts along the gene. Using the April 2000 update of the p53 mutation database of the International Agency for Research on Cancer together with the primary literature, we confirm that the frequency of p53 G-->T transversions in lung cancer of smokers is about three times higher than their frequency in lung cancer of nonsmokers and in most other smoke-unrelated cancers. In contrast, the frequency of C-->A transversions, the DNA-strand mirror counterpart of G-->T transversions, appears to be similar in virtually all human cancers. Along with other data, this strand bias leads us to suggest that smoking may inhibit repair of G-->T primary lesions on the non-transcribed strand. As to the origin of G-->T primary lesions in the p53 gene, we unexpectedly found that cell lines derived from lung cancers, but not from other cancers, demonstrate significant additional excess of G-->T transversions when compared to p53 mutations in parent primary tumors. A detailed codon-by-codon comparison provides evidence in favor of the in vitro origin of this culture-associated G-->T augmentation. Since in culture lung cancer cell lines are not exposed to the carcinogens from smoke, one would rather ascribe these new G-->T transversions to some other mutagens such as, for example, reactive oxygen and nitrogen species. These results are consistent with our previous report [Proc. Natl. Acad. Sci. U.S.A. 97 (2000) 12244], and suggest that other factors, in addition to the direct mutagenic action of PAH-like carcinogens, contribute to p53 mutation-associated lung malignancy.
Rodin
Sergei N
SN
Department of Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA. srodin@coh.org
Rodin
Andrew S
AS
D000225:Adenine; D016009:Chi-Square Distribution; D004260:DNA Repair / Q000235:genetics; D030541:Databases, Genetic; D005787:Gene Frequency; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics*; D009154:Mutation; D017354:Point Mutation; D011084:Polycyclic Aromatic Hydrocarbons / Q000009:adverse effects; D012907:Smoking; D013941:Thymine; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D011084:Polycyclic Aromatic Hydrocarbons; D016159:Tumor Suppressor Protein p53; D000225:Adenine; D013941:Thymine