N‐methylnitrosourea—lnduced Ki‐ras codon 12 mutations: Early events in mouse thymic lymphomas

Abstract

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.

Specific N-ras mutation in bone marrow within 48 H of 7,12-dimethylbenz[a]anthracene treatment in Huggins-Sugiyama rat leukemogenesis

“…Ki-rus mutations are found in N-nitroso-bis(2-oxopropyl)amin+induced hyperplasia of the pancreas in hamsters [23] and in aberrant crypt foci and adenomas during azoxymethane-induced colon carcinogenesis in rats [24]. Ki-rus mutation also appears in the early stage of N-methylnitrosoureainduced thymic lymphoma [25]. Furthermore, some studies have shown that mutations in rus family genes occur before the appearance of histopathological changes.…”

Use of N-methyl-N-nitrosourea treatment of fertilized egg cells for saturation mutagenesis of rice

“…O 6 -methylguanine, induced in DNA by MNU treatment, gave rise to GC to AT transition mutations via mispairing with thymine during DNA replication (Cooke et al 2003, Engelbergs et al 2000. A number of studies on alkyl nitrosourea induced rodent tumors have shown that methylating N-nitroso carcinogens almost exclusively induced GC to AT transitions in the genes analyzed (Calvert et al 1996, Guzman et al 1992, Newcomb et al 1995, Ohgaki et al 1992, Sukumar et al 1983, Sukumar and Barbacid 1990, You et al 1989, Zaidi et al 1995, Zarbl et al 1985.…”

Influence of DNA Repair on Nonlinear Dose-Responses for Mutation

“…Furthermore, O 6 MeG has been implicated in the MNU-induced transformation of ras proto-oncogenes (Jacoby et al ., 1992; Mariyama et al ., 1989; Newcomb et al ., 1995; Sukumar, 1989) and in cancer initiation (Becker et al ., 1996; Bos, 1989). O 6 MeG is efficiently repaired by O 6 MeG-DNA methyltransferase (MGMT) in a suicide reaction that inactivates MGMT (Kaina et al ., 2007).…”