Radon and lung carcinogenesis: mutability of p53 codons 249 and 250 to 238Pu alpha-particles in human bronchial epithelial cells.
Radon-222, a decay product of uranium-238 and a source of high linear energy transfer (LET) alpha-particles, has been implicated in the increased risk of lung cancer in uranium miners as well as non-miners. p53 mutation spectrum studies of radon-associated lung cancer have failed to show any specific mutational hot spot with the exception of a single study in which 31% of squamous cell and large cell lung cancers from uranium miners showed a p53 codon 249 AGGarg --> ATGmet mutation. Although the results of laboratory studies indicate that double-strand breaks and deletions are the principal genetic alterations caused by alpha-particles, uncertainty still prevails in the description of DNA damage in radon-associated human lung cancer. In the present study, we have evaluated the mutability of p53 codons 249 and 250 to alpha-particles in normal human bronchial epithelial (NHBE) cells using a highly sensitive genotypic mutation assay. Exposure of NHBE cells to a total dose of 4 Gy (equivalent to approximately 1460 working level months in uranium mining) of high LET alpha-radiation induced codon 249 AGG --> AAG transitions and codon 250 CCC --> ACC transversions with absolute mutation frequencies of 3.6 x 10(-7) and 3.8 x 10(-7) respectively. This mutation spectrum is consistent with our previous report of radon-associated human lung cancer.
Hussain
S P
SP
Laboratory of Human Carcinogenesis, NCI, NIH, Bethesda, MD 20892-4255, USA.
Kennedy
C H
CH
Amstad
P
P
Lui
H
H
Lechner
J F
JF
Harris
C C
CC
D000293:Adolescent; D003062:Codon / Q000235:genetics / Q000528:radiation effects*; D016158:Genes, p53 / Q000235:genetics / Q000528:radiation effects*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D016296:Mutagenesis; D009152:Mutagenicity Tests; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D011886:Radon / Q000633:toxicity*
D003062:Codon; D011886:Radon