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

Hirayama, Yoshikazu; Wakazono, Kuniko; Yamamoto, Masami; Kitano, Motoo; Tatematsu, Masae; Nagao, Minako; Sügimura, Takashi

doi:10.1002/(sici)1098-2744(199905)25:1<42::aid-mc5>3.0.co;2-f

Cited by 14 publications

(14 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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 )…”

Section: Discussionsupporting

confidence: 58%

See 1 more Smart Citation

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

et al. 2005

Self Cite

View full text Add to dashboard Cite

N-Methyl-N′ ′ ′ ′-nitro-N-nitrosoguanidine (MNNG)-induced rat stomach carcinomas are considered to be a good model for differentiatedtype human stomach carcinomas. However, as for their molecular basis, only infrequent mutations of Catnb (β β β β-catenin) and Trp53 (p53) have been observed. Here, we carried out a whole-genome analysis of loss of heterozygosity (LOH) using 21 stomach carcinomas induced by MNNG in F 1 hybrids of ACI and BUF rats, and also analyzed promoter methylation of four tumor-suppressor genes. LOH analysis was performed using 130 polymorphic markers covering rat chromosomes 1-20 with an average interval of 20 Mbp. Despite adapting conditions so that LOH could be detected with up to a 50% contamination of stromal cells, no LOH was detected at any loci. CpG islands in putative promoter regions of four tumor-suppressor genes, Cdh1 (E-cadherin), Cdkn2a (p16), Mlh1, and Rassf1a, were analyzed by methylation-specific polymerase chain reaction (PCR). However, no methylation was detected. In contrast, the promoter region of Pgc (pepsinogen C), which lacks a CpG island, was methylated in all 21-cancer samples. These results indicated that LOH spanning a chromosomal region larger than 30 -40 Mbp or silencing of Cdh1, Cdkn2a, Mlh1, and Rassf1a, was not involved in MNNG-induced rat stomach carcinomas. The search for other genes involved in these carcinomas needs to be continued. (1) have proven to be good models for human differentiated-type gastric cancers.(2-5) Rat stomach cancers have histological features in common with human cancers, and closely reflect the effects of various tumor promoters, for example salt and sex hormones, and of preventive agents such as green tea components.(2-4) Based on oligonucleotide microarray analysis, it was found that rat stomach cancers had similar expression profiles to human stomach cancers; that is, genes involved in differentiated phenotypes of the stomach are downregulated, and genes involved in extracellular matrix remodeling and immune responses are upregulated. Clarification of molecular mechanisms in MNNG-induced rat stomach cancers is important for identifying novel molecular mechanisms in human stomach cancers. We have therefore worked to analyze genetic alternations in rat stomach cancers. With regard to the activation of oncogenes, Catnb (β-catenin) mutations were observed in high-grade lesions, although such lesions were infrequent (4/22).(6) Mutations of Kras2 (K-ras) and amplification of Fgfr2 (K-sam) and Erbb2 were not detected in 10 cancers, and are considered to be very infrequent.(7) With regard to the inactivation of tumor-suppressor genes, Trp53 (p53) mutations were infrequent (1/10), and microsatellite instability was absent. Regarding loss of heterozygosity (LOH), no information is available for rat stomach cancers, whereas frequent LOH has been observed in human stomach cancers.(8-10) Cancers induced in defined genetic and environmental conditions have limited sets of genetic alterations.(11-13) LOH analysis in MNNG-induced rat stomach cancer...

show abstract

Section: Discussionsupporting

confidence: 58%

“…( 7 ) With regard to the inactivation of tumor‐suppressor genes, Trp53 ( p53 ) mutations were infrequent (1/10), and microsatellite instability was absent. ( 7 )…”

mentioning

confidence: 99%

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

et al. 2005

Self Cite

View full text Add to dashboard Cite

show abstract

“…Hirayama et al reported no amplification of K-sam or cerbB-2 in 7 rat adenocarcinomas (Hirayama et al, 1999b) and no microsatellite alterations in 12 loci in nine cases (Hirayama et al, 1999b). CONCLUSIONS Many animal models for stomach cancers have been established using rats, dogs, and mice.…”

Section: Other Gene Alterationsmentioning

confidence: 99%

Animal Models of Stomach Carcinogenesis

2007

Self Cite

View full text Add to dashboard Cite

Although incidences of stomach cancer have decreased over the past several decades, the disease remains an important public health problem. To identify pathological and molecular biochemical mechanisms, various experimental animal models have been established in rats and mice with chemical carcinogens including N -methyl-N -nitro-N -nitrosoguanidine (MNNG) and N-methyl-N-nitrosourea (MNU). Helicobacter pylori (H. pylori) is one of the most important factors for human stomach disorders, including neoplasia, and the H. pylori-infected and carcinogen-treated Mongolian gerbil (MG) has proven very useful for analyses of underlying processes. The findings with this model support the hypothesis that intestinal metaplasia is important not as a precancerous lesion but rather as a paracancerous condition and that intestinalization of stomach cancer progresses with chronic inflammation. Furthermore, dose-dependent enhancing effects of salt on stomach carcinogenesis could be demonstrated in MGs treated with MNU and H. pylori modifying surface mucous gel layer. H. pylori itself only causes chronic inflammation and acts as a promoter of stomach carcinogenesis in experimental models. Based on the precise pathological diagnosis of stomach lesions such as noncancerous heterotopic proliferative glands (HPG) and adenocarcinomas, a basis for understanding mechanisms of carcinogenesis has been established on which chemoprevention can be modeled.Keywords. Mouse; rat; Mongolian gerbil; Animal model; Helicobacter pylori; gastric; intestinal metaplasia INTRODUCTION Stomach cancer incidence and mortality have fallen dramatically in the United States and western countries over the past several decades. Nonetheless, it remains a major public health issue as the 4th most common cancer and the 2nd leading cause of cancer death worldwide (Crew and Neugut, 2004). In Japan, stomach cancer remains an important medical problem and its prevention is one of the most important aspects of cancer control strategy, despite its decreasing trend (Tsugane, 2005). Many pathological and biological analyses of stomach carcinomas, including precancerous lesions, have been performed with human samples and experimental animals. In this article, we review the history of stomach carcinoma research from the viewpoint of basic aspects, concentrating especial attention on pathological and biological findings and results for various important modifying factors.

show abstract

“…[16][17][18][19][20] However, there has been little information generated regarding the molecular basis of the process. We previously examined genetic alterations that have been reported in human stomach cancers, using DNA samples extracted from cancers 21) and observed only a few (one in 10 cancers) mutations of the p53 gene at the second position of codon 171 (Val→Glu) and no mutations in codons 12, 13, or 61 of Ki-ras or in the N-terminal phosphorylation sites of the β-catenin gene. Furthermore, there was no apparent amplification of the K-sam or c-erbB-2 genes and no microsatellite alterations.…”

mentioning

confidence: 99%

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

Tsukamoto¹,

Yamamoto²,

Ogasawara³

et al. 2003

Cancer Science

Self Cite

View full text Add to dashboard Cite

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

Cited by 14 publications

References 19 publications

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

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

Animal Models of Stomach Carcinogenesis

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

Contact Info

Product

Resources

About