N-methylnitrosourea-induced Ki-ras codon 12 mutations: early events in mouse thymic lymphomas.
N-Methylnitrosourea (NMU)-induced codon 12 Ki-ras mutations were analyzed in premalignant thymic lymphomas from C57BL/6J mice by using a selective polymerase chain reaction amplification strategy. The frequency of codon 12 Ki-ras mutations was 67% (16 of 24) in NMU-treated animals with premalignant stage I disease. Previously, animals with different stages of disease had been analyzed for cytogenetic changes and for mutations in the p53 tumor suppressor gene. The genetic changes observed were early-activating codon 12 G35-->A transition mutations of the Ki-ras gene, followed closely by trisomy 15 and infrequent mutation of the p53 gene late in tumor development. The consistent and early detection of Ki-ras mutations in NMU-treated animals but not in untreated controls suggests that the mutations result from direct carcinogen exposure. Alternate pathways of NMU-induced thymic lymphomagenesis were implicated. One pathway involved putative NMU-induced mutations in other, non-ras oncogenes that cooperate with trisomy 15 to produce similar T-cell tumors. The frequency of p53 gene mutations in human and murine T-cell tumors is similar but low.
Newcomb
E W
EW
Department of Pathology, New York University Medical Center, New York 10016, USA.
Bayona
W
W
Pisharody
S
S
D000818:Animals; D001483:Base Sequence; D003062:Codon / Q000187:drug effects*; D005260:Female; D011905:Genes, ras / Q000187:drug effects*; D008223:Lymphoma / Q000235:genetics*; D008770:Methylnitrosourea / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions / Q000235:genetics*; D013950:Thymus Gland / Q000187:drug effects; D013953:Thymus Neoplasms / Q000235:genetics*
D003062:Codon; D008770:Methylnitrosourea