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.