Chromosomal mapping of genes controlling development, histological grade, depth of invasion, and size of rat stomach carcinomas

Rat stomach cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) are widely used as a model of differentiated-type human stomach cancers. AC I/N (ACI) 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 ca rcinogenicity test by giving MNNG in drinking water to 117 male ACI x (ACIx BUF)F-1 backcross rats. Each of 100 effective rats was diagnosed for its "c arcinoma development" and when it was bearing stomach carcinoma(s), for his tological grade, depth of invasion, and size and number of tunors. Carcinom a development was diagnosed based both on the age of the rat and on the pre sence of stomach carcinoma(s), Linkage analysis was performed with the geno types of 161 loci, covering 1637 cM of the rat genome. Contrary to our orig inal expectations, the most influential gene was the one on chromosome (chr .) 15, Gastric cancer susceptibility gene I (Gcs1), which confers susceptib ility to stomach carcinogenesis (LOD, 3.8) with a dominant BUF allele by pr omoting conversion from adenomas to carcinomas. Two resistance genes on chr . 4 and chr. 3, Gastric cancer resistance gene 1 (Gcr1) and Gcr2, were show n to confer dominant resistance (LOD, 2.7 and 2.6, respectively), Gcs1, Ger 1, and Gcr2 exerted additive effects on the development of stomach carcinom as. A gene on chr. 16, Ger3, was indicated to reduce the depth of invasion (LOD, 2.2) and sizes of tumors (LOD, 1.9). No linkage was obtained using th e number of tumors. These findings show that the coordinate effect of a sus ceptibility gene, Gcr1, and two resistance genes, Gcr1 and Gcr2, is respons ible for the development of MNNG-induced stomach carcinomas and that Gcr3 i s responsible for the growth of a stomach carcinoma, reflected in the depth of invasion and in the tumor size.