1. Cancer Res. 2000 Feb 15;60(4):1092-6.
Chromosomal mapping of genes controlling development, histological grade, depth
of invasion, and size of rat stomach carcinomas.
Ushijima T(1), Yamamoto M, Suzui M, Kuramoto T, Yoshida Y, Nomoto T, Tatematsu M,
Sugimura T, Nagao M.
Author information:
(1)Carcinogenesis Division, National Cancer Center Research Institute, Tokyo,
Japan. tushijim@ncc.go.jp
Rat stomach cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) are
widely used as a model of differentiated-type human stomach cancers. ACI/N (ACT)
rats are susceptible and BUF/Nac (BUF) rats are resistant to MNNG-induced stomach
carcinogenesis, and the presence of an autosomal gene with a dominant BUF allele
has been suggested. In this study, we performed a carcinogenicity test by giving
MNNG in drinking water to 117 male ACI x (ACIxBUF)F1 backcross rats. Each of 100
effective rats was diagnosed for its "carcinoma development" and when it was
bearing stomach carcinoma(s), for histological grade, depth of invasion, and size
and number of tumors. Carcinoma development was diagnosed based both on the age
of the rat and on the presence of stomach carcinoma(s). Linkage analysis was
performed with the genotypes of 161 loci, covering 1637 cM of the rat genome.
Contrary to our original expectations, the most influential gene was the one on
chromosome (chr.) 15, Gastric cancer susceptibility gene 1 (Gcs1), which confers
susceptibility to stomach carcinogenesis (LOD, 3.8) with a dominant BUF allele by
promoting conversion from adenomas to carcinomas. Two resistance genes on chr. 4
and chr. 3, Gastric cancer resistance gene 1 (Gcr1) and Gcr2, were shown to
confer dominant resistance (LOD, 2.7 and 2.6, respectively). Gcs1, Gcr1, and Gcr2
exerted additive effects on the development of stomach carcinomas. A gene on chr.
16, Gcr3, was indicated to reduce the depth of invasion (LOD, 2.2) and sizes of
tumors (LOD, 1.9). No linkage was obtained using the number of tumors. These
findings show that the coordinate effect of a susceptibility gene, Gcs1, and two
resistance genes, Gcr1 and Gcr2, is responsible for the development of
MNNG-induced stomach carcinomas and that Gcr3 is responsible for the growth of a
stomach carcinoma, reflected in the depth of invasion and in the tumor size.
PMID: 10706129 [PubMed - indexed for MEDLINE]
PUBMED: 10706129
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