Mutation frequencies in murine keratinocytes as a function of carcinogenic status.
A link between genetic abnormalities and carcinogenesis is well established. It follows that a correlation exists between mutation frequency and malignant progression. We have determined the spontaneous and DNA damage-induced mutation frequencies for a series of cell lines derived from SENCAR mouse keratinocytes at various stages of malignant progression. Nontumorigenic mouse keratinocytes (3PC), papillomas (MT1/2), squamous-cell carcinomas (CH72), and spindle-cell carcinomas (CH72T4) were transfected with damaged or undamaged shuttle vectors containing a supF mutation reporter gene. The plasmid mutation frequencies were determined by blue/white screening. The spontaneous plasmid mutation frequency of the squamous-cell carcinoma line was slightly higher than the mutation frequencies of the other cell lines tested. The DNA damage induced by triplex-directed psoralen crosslinks increased the mutation frequencies sixfold to eighteenfold in all cell lines tested, with no significant differences among the cell lines. Sequence analyses revealed that the spindle-cell carcinoma line had a different spontaneous mutation spectrum from the other cell lines. DNA damage-induced mutations were predominantly point mutations at the triplex-duplex junction in all of the cell lines tested, as expected. These data suggested that a strong mutator phenotype was not required for progression to an advanced malignant phenotype in our model system.
Christensen
Laura A
LA
Department of Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas, USA.
Conti
Claudio J
CJ
Fischer
Susan M
SM
Vasquez
Karen M
KM
D000818:Animals; D001483:Base Sequence; D002277:Carcinoma / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology; D002478:Cells, Cultured; D003432:Cross-Linking Reagents / Q000633:toxicity; D004249:DNA Damage / Q000235:genetics; D005363:Ficusin / Q000633:toxicity; D005787:Gene Frequency; D016153:Genes, Suppressor; D015603:Keratinocytes / Q000473:pathology* / Q000502:physiology; D051379:Mice; D018632:Mice, Inbred SENCAR; D008969:Molecular Sequence Data; D009154:Mutation; D010212:Papilloma / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D012343:RNA, Transfer / Q000235:genetics; D012016:Reference Values
D003432:Cross-Linking Reagents; C096275:supF tRNA; D012343:RNA, Transfer; D005363:Ficusin