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.
Molecular Hepatology Laboratory, Massachusetts General Hospital Cancer Center, Charlestown 02129.
A
A
Puisieux
S
S
Lim
J
J
Groopman
M
M
Ozturk
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