Activation of the Ki-ras gene in spontaneous and chemically induced lung tumors in CD-1 mice.
As part of an evaluation of the effectiveness of using ras mutation analysis for distinguishing carcinogen-induced from spontaneous tumors, we examined the profile of ras gene point mutations in spontaneous, 7,12-dimethylbenz[a]anthracene (DMBA)-induced, and N-nitrosodiethylamine (DEN)-induced lung tumors from Crl:CD-1(ICR)BR (CD-1) mice. Although all of the lung tumors were assayed for mutations in the Ha-ras, Ki-ras, and N-ras genes (codons 12, 13, and 61), only Ki-ras mutations were found, which is consistent with other studies that have noted a strong preference for Ki-ras gene activation in mouse, rat, and human lung tumors. We found that spontaneous CD-1 mouse lung tumors had a very high frequency of Ki-ras gene activation (17 of 20 tumors; 85%), distributed among codons 12 (5 of 20), 13 (1 of 20), and 61 (11 of 20). DMBA-induced lung tumors had a slightly higher frequency of Ki-ras gene mutations (16 of 16; 100%), again distributed among codons 12 (5 of 16), 13 (2 of 16), and 61 (9 of 16). However, seven of the DMBA tumors had mutations qualitatively different from those found in spontaneous tumors. In contrast to DMBA-induced tumors, DEN-induced tumors had a lower frequency of Ki-ras mutations (36%) when compared with spontaneous lung tumors, suggesting that DEN primarily induces lung carcinogenesis by a mechanism other than ras gene activation. Thus, although spontaneous and induced CD-1 mouse lung tumors have a strong tissue-specific preference for carrying an activated Ki-ras gene, the nature of the initiating carcinogen can influence the frequency or profile of Ki-ras mutations.
Manam
S
S
Department of Safety Assessment, Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
Storer
R D
RD
Prahalada
S
S
Leander
K R
KR
Kraynak
A R
AR
Hammermeister
C L
CL
Joslyn
D J
DJ
Ledwith
B J
BJ
van Zwieten
M J
MJ
Bradley
M O
MO
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D004252:DNA Mutational Analysis; D004052:Diethylnitrosamine / Q000633:toxicity; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D011905:Genes, ras / Q000187:drug effects*; D006881:Hydroxyacetylaminofluorene; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics*; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D015533:Transcriptional Activation; D014162:Transfection; D010128:p-Aminoazobenzene / Q000633:toxicity
D004052:Diethylnitrosamine; D006881:Hydroxyacetylaminofluorene; D015127:9,10-Dimethyl-1,2-benzanthracene; D010128:p-Aminoazobenzene