p53 mutations in lung cancers from Japanese mustard gas workers.
Mustard gas (MG) is a mutagenic and carcinogenic alkylating agent, and is a known risk factor for occupational lung cancer. Our hypothesis is that lung cancers from MG workers contain mutations (G:C to A:T transitions) as the result of MG-produced DNA promutagenic adducts in the p53 tumor suppressor gene. We analyzed 12 primary lung cancers from Japanese MG factory workers and 12 lung cancers from non-exposed individuals. Genomic DNA was isolated from archival paraffin-embedded tissues. Exons 5-8 were amplified by polymerase chain reaction using p53-specific primers, and sequenced by dideoxy termination methods. Six out of 12 lung cancers from MG workers contained a total of eight somatic point mutations: two cases had double G:C to A:T transitions; one had a G:C to T:A transversion; one case had an A:T to G:C transition; and two cases had single base deletions. Four of the six mutated purines occurred on the non-transcribed, DNA-coding strand. Out of 12 unexposed cases, there were six single base mutations in six cancers, and no double mutations. The p53 mutational frequency in the MG-exposed cases is similar to the non-exposed controls and the usual smoking-related lung cancers reported previously. However, the distinctive double mutations (G:C to A:T transition) observed in two cases are unusual and may be related to MG exposure.
Takeshima
Y
Y
Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Inai
K
K
Bennett
W P
WP
Metcalf
R A
RA
Welsh
J A
JA
Yonehara
S
S
Hayashi
Y
Y
Fujihara
M
M
Yamakido
M
M
Akiyama
M
M
D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D003062:Codon; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects / Q000235:genetics; D005091:Exons; D016158:Genes, p53 / Q000187:drug effects*; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009151:Mustard Gas / Q000009:adverse effects*; D009154:Mutation; D009784:Occupational Diseases / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics*; D017354:Point Mutation
D003062:Codon; D004273:DNA, Neoplasm; D009151:Mustard Gas