Selective targeting of p53 gene mutational hotspots in human cancers by etiologically defined carcinogens.
In lung and liver cancers, p53 mutations are mostly G:C to T:A transversions. This type of mutation is known to be induced by benzo(a)pyrene and aflatoxin B1 which are associated with the etiology of lung and liver cancers, respectively. Using a novel assay based on DNA polymerase fingerprint analysis, we identified p53 nucleotides targeted by these carcinogens. Thirteen of 14 nucleotide residues of the p53 gene which underwent G:C to T:A mutations in lung cancers were targeted by benzo(a)pyrene. Similarly, aflatoxin B1 formed adducts at a mutational hotspot specific for liver cancer. The same nucleotide (third base of codon 249), which mutates rarely in lung cancers, was not a target for benzo(a)pyrene. These in vitro observations indicate that p53 mutational hotspots identified in different tumors are selected targets specifically for the etiologically defined environmental carcinogens.
Puisieux
A
A
Molecular Hepatology Laboratory, Massachusetts General Hospital Cancer Center, Charlestown 02129.
Lim
S
S
Groopman
J
J
Ozturk
M
M
D016604:Aflatoxin B1 / Q000378:metabolism*; D001483:Base Sequence; D001564:Benzo(a)pyrene / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D016172:DNA Fingerprinting; D016158:Genes, p53; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*
D001564:Benzo(a)pyrene; D004247:DNA; D016604:Aflatoxin B1