Tissue-specific activating mutations of Ha- and Ki-ras oncogenes in skin, lung, and liver tumors induced in mice following transplacental exposure to DMBA.
Transplacental carcinogenesis represents a good model in which to study the involvement of tissue-specific oncogene activation in carcinogenesis because a single exposure to a carcinogen induces tumors at various sites. We tested tumors of the skin, liver, and lung produced in mice after transplacental 7,12-dimethylbenz[a]-anthracene (DMBA) exposure for possible activation of ras genes. XbaI restriction fragment-length polymorphism analysis has shown that exposure to DMBA in utero may result in appearance of A----T transversion at the second position of codon 61 of Ha-ras oncogene in skin and liver tumors but not in lung tumors. Moreover, DNA samples isolated from spontaneous and DMBA-induced lung and liver tumors were analyzed for mutations at the same position of Ki-ras oncogene using differential hybridization with specific oligonucleotides. Among five spontaneous lung tumors, three cases of A----G transition, and one case of A----T transversion were found, whereas four of ten lung tumors of DMBA-treated animals were positive for A----T mutation. No Ki-ras mutation was detected in one spontaneous and four DMBA-induced hepatomas. In two cases, we revealed Ki-ras A----T mutation in the lung tumor and Ha-ras mutation in the liver tumor taken from the same animal. These results indicate first that DMBA treatment may induce A----T mutation at the second position of codon 61 both in Ha-ras and in Ki-ras and, second, that the role of different activated oncogenes in carcinogenesis may differ, depending on the tissue in which the tumor develops.
Loktionov
A
A
International Agency for Research on Cancer, Lyon, France.
Hollstein
M
M
Martel
N
N
Galendo
D
D
Cabral
J R
JR
Tomatis
L
L
Yamasaki
H
H
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D003062:Codon; D005260:Female; D005315:Fetal Diseases / Q000139:chemically induced; D011905:Genes, ras; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics*; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics*; D051379:Mice; D009154:Mutation; D009928:Organ Specificity; D012150:Polymorphism, Restriction Fragment Length; D011247:Pregnancy; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics*
D003062:Codon; D015127:9,10-Dimethyl-1,2-benzanthracene