Genetic resolution of susceptibility to cancer--new perspectives

Neoplastic development is under strong genetic control, which results in large differences in tumor susceptibility between individuals of the same species. These differences are caused by tumor susceptibility genes (TSGs). The characteristic features of TSGs are frequent polymorphism, influence on specific aspects of the tumorigenic process, and tissue specificity. In contrast to cellular oncogenes and tumor suppressor genes, which in most instances require somatic alterations to become engaged in the tumorigenic process, the allele-specific effects of TSGs are encoded in the germ-line. Until recently, the TSGs have remained virtually unknown despite many efforts to map them. Their multiplicity and incomplete penetrance defied the available genetic methods. Therefore a novel genetic tool, the Recombinant Congenic Strain (RCS) has been developed in the mouse (P. Demant and A.A.M Hart, Immunogenetics 24:416-422), which allows dissection of multigenic control and mapping of the genes contributing to it. When applied to colon tumors, the RCS revealed separate genetic control for tumor numbers and tumor size, and allowed mapping of several TSGs. The presently available RC strains allow the genetic and functional dissection of virtually all major types of mouse tumors. This opens the possibility to map, within a relatively short period, the TSGs for various organs, to study the functional effects of individual TSGs and the possible interactions of this new class of genes with the known oncogenes and tumor suppressor genes. The extensive information about the chromosomal homologies between man and mouse will facilitate the search for their human counterparts once the TSGs in mouse are mapped.