Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53.
Cigarette smoke carcinogens such as benzo[a]pyrene are implicated in the development of lung cancer. The distribution of benzo[a]pyrene diol epoxide (BPDE) adducts along exons of the P53 gene in BPDE-treated HeLa cells and bronchial epithelial cells was mapped at nucleotide resolution. Strong and selective adduct formation occurred at guanine positions in codons 157, 248, and 273. These same positions are the major mutational hotspots in human lung cancers. Thus, targeted adduct formation rather than phenotypic selection appears to shape the P53 mutational spectrum in lung cancer. These results provide a direct etiological link between a defined chemical carcinogen and human cancer.
Denissenko
M F
MF
Department of Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
Pao
A
A
Tang
M
M
Pfeifer
G P
GP
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000378:metabolism / Q000633:toxicity*; D001980:Bronchi; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D002478:Cells, Cultured; D003062:Codon; D018736:DNA Adducts / Q000378:metabolism*; D015226:Dinucleoside Phosphates / Q000378:metabolism; D005091:Exons; D005347:Fibroblasts; D016158:Genes, p53; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics*; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity; D009154:Mutation; D010947:Plants, Toxic; D012906:Smoke / Q000009:adverse effects; D014026:Nicotiana
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D002273:Carcinogens; D003062:Codon; D018736:DNA Adducts; D015226:Dinucleoside Phosphates; D009153:Mutagens; D012906:Smoke; C015772:CpG dinucleotide