N-ras mutation in ultraviolet radiation-induced murine skin cancers.
UV radiation is a potent DNA-damaging agent and a known inducer of skin cancer in experimental animals. To elucidate the role of oncogenes in UV carcinogenesis, we analyzed UV-induced murine skin tumors for mutations in codon 12, 13, or 61 of Ha-ras, Ki-ras, and N-ras oncogenes by amplification of genomic tumor DNAs by the polymerase chain reaction followed by dot-blot hybridization to synthetic oligonucleotide probes designed to detect single base-pair mutations. In addition to UV-induced C3H mouse skin tumors, we also analyzed skin tumors induced in the same strain of mice by other carcinogenic agents such as 8-methoxypsoralen + UVA, angelicin + UVA, dimethylbenz-[a]anthracene + UV + croton oil, and 4-nitroquinoline-1-oxide. We found that 4 of 20 UV-induced skin tumors contained either C----A or A----G base substitutions at N-ras codon 61. In addition, 2 of 5 melanomas possessed a G----A transition in N-ras codon 13 and an A----T transversion in N-ras codon 61, respectively. Interestingly, none of the 8-methoxypsoralen + UVA- or angelicin + UVA-induced tumors we analyzed contained mutations in any of the ras genes. However, 1 of 4 4-nitroquinoline-1-oxide-induced tumors exhibited a G----T transversion at Ki-ras codon 12, a potential site for formation of a 4-nitroquinoline-1-oxide adduct with a guanine residue. We also found that 2 nonmelanoma tumors induced by dimethylbenz[a]anthracene + UV + croton oil contained an A----T transversion at Ha-ras codon 61 position 2, which is characteristic of most dimethylbenz[a]anthracene-induced tumors. These results suggest that UV-induced C3H mouse tumors display mutations preferentially in the N-ras oncogene. Since most N-ras mutations in UV-induced tumors occurred opposite dipyrimidine sequences (T-T or C-C), one can infer that these sites are the targets for UV-induced mutation and transformation.
Pierceall
W E
WE
Department of Immunology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Kripke
M L
ML
Ananthaswamy
H N
HN
D000818:Animals; D001483:Base Sequence; D003062:Codon / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D011905:Genes, ras / Q000235:genetics / Q000528:radiation effects*; D015151:Immunoblotting; D051379:Mice; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics*
D003062:Codon; D004273:DNA, Neoplasm