Targeting of lung cancer mutational hotspots by polycyclic aromatic hydrocarbons.
BACKGROUND
Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in combustion products of organic matter, including cigarette smoke. Metabolically activated diol epoxides of these compounds, including benzo[a]pyrene diol epoxide (B[a]PDE), have been suggested as causative agents in the development of lung cancer. We previously mapped the distribution of B[a]PDE adducts within the p53 tumor suppressor gene (also known as TP53), which is mutated in 60% of human lung cancers, and found that B[a]PDE adducts preferentially form at lung cancer mutational hotspots (codons 154, 157, 158, 245, 248, and 273). Other PAHs may be important in lung cancer as well.


METHODS
Here we have mapped the distribution of adducts induced by diol epoxides of additional PAHs: chrysene (CDE), 5-methylchrysene (5-MCDE), 6-methylchrysene (6-MCDE), benzo[c]phenanthrene (B[c]PDE), and benzo[g]chrysene (B[g]CDE) within exons 5, 7, and 8 of the p53 gene in human bronchial epithelial cells.


RESULTS
CDE exposure produced only low levels of adducts. Exposure of cells to the other activated PAHs resulted in DNA damage patterns similar to those previously observed with B[a]PDE but with some distinct differences. 5-MCDE, 6-MCDE, B[g]CDE, and B[c]PDE efficiently induced adducts at guanines within codons 154, 156, 157, 158, and 159 of exon 5, codons 237, 245 and 248 of exon 7, and codon 273 of exon 8, but the relative levels of adducts at each site varied for each compound. B[g]CDE, B[c]PDE, and 5-MCDE induced damage at codon 158 more selectively than 6-MCDE or B[a]PDE. The sites most strongly involved in PAH adduct formation were also the sites of highest mutation frequency (codons 157, 158, 245, 248, and 273).


CONCLUSIONS
The data suggest that PAHs contribute to the mutational spectrum in human lung cancer.
Smith
L E
LE
Department of Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
Denissenko
M F
MF
Bennett
W P
WP
Li
H
H
Amin
S
S
Tang
M
M
Pfeifer
G P
GP
D001483:Base Sequence; D001580:Benzopyrenes / Q000009:adverse effects; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism; D002273:Carcinogens / Q000009:adverse effects*; D002478:Cells, Cultured; D002911:Chrysenes / Q000009:adverse effects; D003062:Codon; D018736:DNA Adducts; D004847:Epithelial Cells / Q000187:drug effects; D004852:Epoxy Compounds / Q000009:adverse effects; D016158:Genes, p53; D008175:Lung Neoplasms / Q000139:chemically induced*; D009154:Mutation; D010616:Phenanthrenes / Q000009:adverse effects; D011084:Polycyclic Aromatic Hydrocarbons / Q000009:adverse effects*
D001580:Benzopyrenes; D002273:Carcinogens; D002911:Chrysenes; D003062:Codon; D018736:DNA Adducts; D004852:Epoxy Compounds; D010616:Phenanthrenes; D011084:Polycyclic Aromatic Hydrocarbons