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A novel rat model of hereditary renal cell carcinoma (RC) was found in a rat colony of the SpragueDawley strain in Japan, and named the "Nihon" rat. In this strain, RCs develop from early preneoplastic lesions, which begin to appear at 4 weeks of age, forming adenomas by the age of 16 weeks. The RCs are predominantly of clear cell type. Southern blot, northern blot and SSCP analyses revealed no change in the Tsc1, Tsc2, VHL, and c-Met genes. Thus, the Nihon rat should be a valuable experimental model for understanding renal carcinogenesis, especially clear cell type, which is common among human RCs.Key words: Nihon rats -Tsc2 gene mutant (Eker) rats -Renal carcinogenesis -Hereditary cancer Hereditary cancer was first described in the rat by Eker in 1954.1) The Eker rat model of hereditary renal carcinoma (RC) was the first example of a Mendelian dominantly inherited predisposition to a specific cancer in an experimental animal. In 1994, Hino and colleagues identified a germline mutation in the rat homologous to the human tuberous sclerosis gene (TSC2) as the predisposing Eker gene.2-4) Recently, we found a novel hereditary RC model in the Sprague-Dawley rat in Japan. We have named this novel RC model the Nihon rat. In this report, we described the origin, transmission mode, and phenotypic and molecular features of Nihon rats.All animals were housed individually in stainless steel cages with wood chip bedding in a room controlled at a temperature of 23±2°C, humidity of 55±10%, with a 12 h lighting cycle (from 6 a.m. to 6 p.m.). The rats were fed a standard diet (CR-LPF, Oriental Yeast Co., Ltd., Tokyo) and were allowed tap water ad libitum. Animals were killed by exsanguination under pentobarbital sodium anesthesia. After necropsy, tissues were fixed in 10% neutral buffered formalin, processed to paraffin-embedded blocks, and sectioned at 5 µm using standard procedures. Sections were stained with hematoxylin and eosin for microscopical examination. Midsagittal sections of each kidney were also stained with periodic acid-Schiff (PAS), and with alcian blue for acid mucopolysaccharides. Tail and kidney DNAs from the original (parent) female rat were extracted as reported. [4][5][6][7][8][9] We used Southern blot, northern blot and SSCP analyses to search for mutations of the Tsc1, Tsc2, VHL, and c-Met genes. The gene-specific primers for Tsc1, Tsc2, VHL, and c-Met [Accession No. AB012279 (primer for exon 17), AB012280 (primer for exon 18) and AB012281 (primer for exon 19), kindly provided by Dr. Y. Kikuchi] were described previously. [4][5][6][7][8][9] Bilateral, multicentric renal tubule tumors were found in 15 out of 343 rats during 5 toxicity studies during the safety evaluation of 3 unrelated chemicals in our laboratory, although renal tumors were found in both treated and non-treated rats (Table I). The age of the rats ranged from 7 to 16 weeks at termination of the treatment period in each of the studies (Table I). The rats had all obtained from the same supplier (Clea Japan Inc., Shiga). At necropsy, bilatera...

In the Nihon rat, an established model of hereditary renal cell carcinoma (RCC), the propensity for tumor development, is inherited as an autosomal dominant trait due to a single germline nucleotide insertion mutation in the rat Bhd ortholog. The Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant disease characterized by fibrofolliculoma, pulmonary cysts, spontaneous pneumothorax, and renal neoplasm. The renal lesions of the Nihon rat are characterized, and extrarenal lesions are also described in this work. The earliest lesion of the RCC was identified as an altered tubule at as early as 3 weeks of age and rapidly progressed through adenoma to carcinoma with the primary cell type being clear/acidophilic where some similarities were evident to RCCs in BHD syndrome. The Nihon rats demonstrate a heterotopic ossification within RCCs and three extrarenal lesions, clear cell hyperplasia/adenoma of the endometrium, clear cell change of the epithelium of striated portions of salivary glands, and cardiac rhabdomyomatosis. This rat model of hereditary RCC provides a useful tool for analyzing the series of events leading to renal tumorigenesis and for studying BHD gene functions.

A novel rat model of hereditary renal cell carcinoma (RC) was found in a rat colony of the Sprague-Dawley (SD) strain in Japan, and named the "Nihon" rat in 2000. This study was designed to map the RC susceptibility gene in the Nihon rat using 113 backcross animals. Our present data clearly show that the Nihon gene is genetically linked to interleukin-3 (IL3) gene (χ χ χ χ Hereditary cancer was first described in the rat by Eker and Mossige in 1954 in Oslo.1) The Eker rat model of hereditary renal carcinoma (RC) was the first example of a Mendelian dominantly inherited predisposition to a specific cancer in an experimental animal. We and others identified a germline mutation in the rat homologous to the human tuberous sclerosis gene (TSC2) as the predisposing Eker gene.2-5) Recently, we found a novel hereditary RC model in the Sprague-Dawley (SD) rat in Japan. We have named this novel RC model the Nihon rat. 6) We found that the homozygous mutant condition is lethal at around the 10th day of fetal life. In heterozygotes, RCs develop from early preneoplastic lesions, which begin to appear as early as 3 weeks of age, to adenomas (at 8 weeks of age). By the age 6 months; penetrance for this RC gene is virtually complete.7) The Nihon rat is also an example of a Mendelian dominantly inherited predisposition for development of RCs, but of predominantly clear cell type, and bears a single gene mutation like the Eker rat. 6,7) In the present study, we performed a genetic linkage analysis to the Nihon mutation, as a first step toward its identification.The RC gene of Nihon rat (the Nihon gene) is being carried in the SD strain of rats. A genealogically unrelated strain, inbred Brown Norway (BN) (Charles River Breeding Laboratory), which does not carry the mutations, was used in mating with the Nihon male (Nihon/ +, SD strain) to produce F1 hybrids. Nihon rats are diagnosed by detecting microscopic and/or macroscopic kidney tumors following a unilateral nephrectomy. Then, one heterozygote (Nihon/ +) F1 male (designated BX0011-203 in this study) was in turn mated to BN(+ / +) females to produce backcross progenies. Among 113 backcross [F1{(SD (Nihon/ +)×BN(+ / +)}×BN(+ / +)] animals, 63 ( : 30, : 33, 56%) were histologically found to have multiple renal tumors (adenomas) at 13 weeks of age and 50 ( : 24, : 26, 44%) were negative, which is not significantly different from the expected 50%. Control animals never developed adenomas/RCs at this age.Tail DNAs from 113 backcross animals at 13 weeks of age were extracted by digestion with 2% sodium dodecyl sulfate (SDS)/proteinase K followed by extraction with phenol as reported. 8) DNAs were tested for linkage, noting whether uniquely SD bands of DNA were preferentially found in Nihon gene-bearing rats, with marker DNAs showing polymorphisms between SD and BN strains by polymerase chain reaction (PCR).Rat DNA markers ("MAP PAIRS"), covering whole rat chromosomes, were purchased from Research Genetics, Inc. (Carlsbad, California). PCR was performed in 10 µl of a reaction mixture ...

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