SPONTANEOUS AND INDUCED DOMINANT

27 May

SPONTANEOUS  AND INDUCED  DOMINANT  AND RECESSIVE  GENETIC DISORDERS  ASSOCIATED  WITH HIGH CANCER  INCIDENCE  IN LOWER ANIMALS

Until relatively recently, the germline genetics of cancer in lower animals was far less well stud- ied than that in the human with a few specific exceptions—in particular, strains of mice where genetic factors could be well controlled. However, specific dominant or recessive genes predis- posing to a high incidence of neoplasia have not as yet been frequently seen in animal systems. On the other hand, with the advent of molecular genetic techniques, it has become possible to program genetic factors leading directly to the incidence of specific neoplasms.

Spontaneously Occurring, Dominantly Inherited Neoplasia in Lower Animals

Although our knowledge of dominantly inherited neoplasia in lower animals has not developed rapidly, several excellent systems have been studied rather extensively. In the rodent these in- clude the Eker rat (Eker et al., 1981) and the Min mouse (Moser et al., 1990). In the former example, renal cell carcinomas develop in virtually all rats bearing the dominant mutation by the age of 1 year. In addition, later in the life of these animals, pituitary adenomas, splenic sarcomas, leiomyomas,  and leiomyosarcomas  of the female genital tract can be seen (Hino et al., 1994; Everitt et al., 1995). The gene responsible for this condition is the rat equivalent of the tuberous sclerosis gene (Table 5.6), which is found in the rat on chromosome 10q (Kobayashi et al., 1995; Yeung et al., 1994). Allelic loss at the 10q locus of this gene has been reported in both spontane- ous and chemically induced renal cell carcinomas in the Eker rat (Kubo et al., 1994). However,

the phenotype of tuberous sclerosis in humans (see above) differs from that seen in the Eker rat except for the occurrence of renal neoplasms (Kobayashi et al., 1995).

Another well-studied, dominantly inherited neoplasm is that of intestinal adenomas in Min mice. In these animals, at a young age, multiple adenomas develop throughout the intestine, and the mice are prone to develop mammary neoplasms (Moser et al., 1993). In this condition the gene involved is completely homologous to the APC gene responsible for the development of familial polyposis in the human (Table 5.4). In the original Min mouse, the mutation in the APC gene is a nonsense mutation occurring as the result of a conversion of a leucine (TTG) to a stop (TAG) codon by the transversion from T to A at nucleotide 2549 (Su et al., 1992). Studies on allelic loss of the APC locus indicated that the gene was on mouse chromosome 18 (Luongo et al., 1994). Other genes have been linked to the development of papillomas and squamous cell carcinomas  in the mouse (Lutzner et al., 1985) and thymomas in certain strains of rats (Mat- suyama et al., 1986; Murakumo et al., 1993).

Another well-studied model occurs in fish of the genus Xiphophorus, in which a dominant tumor formation gene (Tu) is under the control of a repressor gene (R). If the R gene is absent, these animals develop fatal melanomas (cf. Anders et al., 1984). The Tu gene appears to encode a membrane receptor tyrosine kinase (cf. Friend, 1993), but the function of the product of the R gene is not known to date. A variety of malignant neoplasms of genetic origin have also been described in the fruit fly, Drosophila melanogaster (Gateff, 1978). More recently, Watson et al. (1994) have reviewed  the more than 50 identified  genes in which loss-of-function  mutations may lead to a variety of abnormalities in cell proliferation, including neoplasia in both the devel- oping and adult Drosophila. Mutations in several genes termed lethal result in neoplastic over- growth of tissues during development, including that of the brain. Abnormalities in several other genes result in tumors of gonadal origin. Several of these genes involved in the development of neoplasms  appear to regulate differentiation  under normal conditions;  but when they are mu- tated, they cause the appearance of benign and malignant neoplasms in the insect.

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