A new class of genes has been recently defined which functions in suppressing tumor development. Such tumor suppressor genes, or anti-oncogenes, have been implicated in tumorigenesis by familial studies in which or inactivation of both wild-type alleles is a prerequisite for tumor development. Although cytogenetic and molecular studies provide convincing evidence that recessive mutations in tumor suppressor genes contribute to human malignancies, especially those with hereditary predispositions, investigations of the molecular and cellular basis for the regulatory role of tumor suppressor genes would be expedited by the ability to carry out studies in a commonly used laboratory animal model system. We have obtained preliminary data in a murine model of lymphomagenesis demonstrating genetic linkage between susceptibility to chemically induced thymic lymphoma and homozygous inheritance of a recessive gene on chromosome 7. These results were obtained by analyzing the incidence and latent period of thymic lymphomas induced by the carcinogen, N-methyl-N-nitrosourea (MNU) in F2 progency derived from F1 hybrids between (highly susceptible) AKR/J mice and (highly resistant)C57L/J mice. The involvement of chromosome 7 is significant in view of the homology shared between regions of murine chromosome 7 and human chromosome 11p. Somatic cell hybridization studies suggest that human chromosome 11 contains at least one tumor suppressor locus. This concept is supported by reports demonstrating that several human neoplasias with hereditary predispositions are associated with recessive genetic lesions on chromosome 11p. Since we have identified an experimental model system that suggests the existence of a tumor suppressor gene on a homologous chromosome in inbred mice, the immediate primary goals of this proposal are to verify the genetic linkage and localize the position of the relevant gene on chromosome 7.
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