Rare mutations ofp53, Ki-ras, and ?-catenin genes and absence of K-sam and c-erbB-2 amplification inN-methyl-N?-N-nitrosoguanidine-induced rat stomach cancers

Abstract

Rat stomach cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) have been widely used as a model for human stomach cancers of the differentiated type. However, there has been little information regarding their molecular basis. In this study, we examined the genetic alterations reported in human stomach cancers in 10 rat stomach cancers that had been induced in male ACI/N rats by administering MNNG in the drinking water. One of the 10 cancers had a mutation of the p53 gene at the second position of codon 171 (Val --> Glu). However, none of the 10 cancers had mutations in codons 12, 13, or 61 of Ki-ras or in the N-terminal phosphorylation sites of the beta-catenin gene. Southern blot analysis showed no amplification of K-sam or c-erbB-2 in the seven cancers examined. Finally, we searched for microsatellite alterations in 12 loci in nine cancers, but no alterations were observed. As these genetic alterations are observed in only a minor fraction of human stomach cancers, further analysis of genetic and epigenetic alterations in MNNG-induced rat stomach cancers is needed to disclose the major mechanisms of stomach carcinogenesis.

β‐Catenin mutations and nuclear accumulation during progression of rat stomach adenocarcinomas

“…6,7,10) The findings here for MNNG-induced rat stomach cancers support the notion that β-catenin mutations can take place in the course of stomach cancer progression. The apparent discrepancy with our previous report 21) might be due to β-catenin activation being confined to a cancer region too small to be detected using DNA extracted from the tumor mass.…”

Whole‐genome analyses of loss of heterozygosity and methylation analysis of four tumor‐suppressor genes in N‐methyl‐N′‐nitro‐N‐nitrosoguanidine‐induced rat stomach carcinomas

“…(6,7) The absence of Kras2 mutations was also confirmed in the 21 tumor samples here by sequencing Kras2 codons 12, 13 and 61 (data not shown). (7) In contrast to the four tumor-suppressor genes, the Pgc promoter region was methylated in all 21 tumors, but not in the noncancerous mucosae of rats with stomach cancers or the normal mucosae of untreated rats. This was in accordance with our previous study in which the methylation of HpaII and HhaI sites in the coding and intronic regions was shown by Southern blot analysis.…”

“…Regarding the mutational activation of oncogenes, in our previous study, Kras2 point mutations were absent, and Catnb mutations were present only in high-grade lesions. (6,7) The absence of Kras2 mutations was also confirmed in the 21 tumor samples here by sequencing Kras2 codons 12, 13 and 61 (data not shown). (7) In contrast to the four tumor-suppressor genes, the Pgc promoter region was methylated in all 21 tumors, but not in the noncancerous mucosae of rats with stomach cancers or the normal mucosae of untreated rats.…”

“…Regarding the mutational activation of oncogenes, in our previous study, Kras2 point mutations were absent, and Catnb mutations were present only in high‐grade lesions. ( 6,7 ) The absence of Kras2 mutations was also confirmed in the 21 tumor samples here by sequencing Kras2 codons 12, 13 and 61 (data not shown). ( 7 )…”

Molecular Mechanism of Gastric Carcinogenesis in Helicobacter pylori-Infected Rodent Models

“…However, MNNG-induced rat stomach adenocarcinomas had a mutation of the p53 gene in only one of 10 cases [82]. In addition, no mutations in exons 5-8 were found in a total of 30 gastric tumors in MNU-treated mice [83].…”