p53 gene mutation analysis in tumors of patients exposed to alpha-particles.
The p53 gene was examined for point mutations in archived, alpha-radiation-associated lung and liver cancers. Lung tumors of 50 uranium miners in Germany were screened by restriction fragment length analysis for the putative hotspot mutation at codon 249 (Arg-->Met) previously detected in a significant fraction of miners from the Colorado Plateau, USA. This mutation has been proposed as a marker of radon exposure. None of the tumors we examined harbored the hotspot mutation. Five of the 50 tumors, however, did indeed harbor exon 7 mutations, as determined by subsequent mutation analysis of exon 7. These mutations were dispersed among various codons and may be attributable to heavy tobacco smoking in this cohort. In support of this interpretation, we found no mutations in exons 5-8 of the p53 gene in 13 iatrogenic liver cancers induced by injection of Thorotrast, an alpha-emitting radiocontrast agent. We propose that if the p53 tumor suppressor gene is a target for the carcinogenic action of alpha-particle radiation, loss of suppressor function may occur preferentially by mechanisms such as intrachromosomal deletions, rather than by base substitution mutations.
Hollstein
M
M
Division of Toxicology and Cancer Risk Factors, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Bartsch
H
H
Wesch
H
H
Kure
E H
EH
Mustonen
R
R
Mühlbauer
K R
KR
Spiethoff
A
A
Wegener
K
K
Wiethege
T
T
Müller
K M
KM
D000368:Aged; D000369:Aged, 80 and over; D000512:Alpha Particles / Q000009:adverse effects*; D003062:Codon / Q000235:genetics; D003287:Contrast Media / Q000009:adverse effects; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics*; D005091:Exons / Q000235:genetics; D016158:Genes, p53 / Q000528:radiation effects*; D005858:Germany / Q000453:epidemiology; D006801:Humans; D008113:Liver Neoplasms / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D008175:Lung Neoplasms / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008906:Mining; D009381:Neoplasms, Radiation-Induced / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D009784:Occupational Diseases / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D017354:Point Mutation; D012150:Polymorphism, Restriction Fragment Length; D011886:Radon / Q000009:adverse effects; D012907:Smoking / Q000009:adverse effects / Q000453:epidemiology / Q000235:genetics; D013911:Thorium Dioxide / Q000009:adverse effects*; D014501:Uranium / Q000009:adverse effects
D003062:Codon; D003287:Contrast Media; D004273:DNA, Neoplasm; D014501:Uranium; D013911:Thorium Dioxide; D011886:Radon