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Educational Session: Studying Genetic Modifiers in Experimental and Human Cancer

Polymorphisms, induced mutations, and karyotypic modifiers of the familial intestinal neoplastic pathway in the mouse.

Univ. of Wisconsin, Madison, WI

Abstract

Genetic differences between inbred strains of the mouse can modify the intestinal cancer phenotype caused by the Min mutation in the gatekeeper gene Apc. The region of the genome responsible for such modification can be mapped through contemporary resources in mouse genetics and genomics. One region that has been studied extensively is Mom1 (1–7). The locus contains a gene encoding the secretory phospholipase Pla2g2a that reduces growth rate and multiplicity of tumors. It also contains at least one other polymorphic determinant, whose molecular identity is not yet known. Further studies in our laboratory and others indicate that the mouse genome contains a number of polymorphic determinants that modify the Min phenotype. It seems possible that the richness of such modifiers will bias the investigator toward regions of the genome containing clusters of determinants. In this scenario, it seems important to consider mutational modifiers, generated either by random point mutagenesis of the mouse germline or by gene targeting (8). Targeted alleles of a number of genes have been observed to modify the Min phenotype. The wealth of this set of modifiers reinforces the impression given by the initial analysis of polymorphic modifiers. Among these are the genes encoding the constitutive and the inducible cyclooxygenases, Cox1and Cox2. A possible paradox exists when considering the mode of action of these two genes and that of the secretory phospholipase. A new class of genetic modifier has been discovered by Kevin Haigis in our laboratory: karyotypic rearrangements (9). The karyotype seems to affect the organization of the interphase nucleus and hence the probability of somatic recombination, the major route by which the gatekeeper gene Apc loses heterozygosity in tumorigenesis.