N ‐methylnitrosourea—lnduced 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 G 35 →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. © 1995 Wiley‐Liss, Inc.