During the development of cancer a series of specific genetic alterations have to occur in a stepwise fashion to transform a normal somatic cell into a malignant tumor cell. These genetic changes can be roughly divided in two groups: mutations in proto-oncogenes that result in a constantly activated gene product and mutations in tumor-suppressor genes that result in loss of function. While oncogenic mutations often have a dominant phenotype and mutation of one allele is sufficient for activation, in general both alleles of a tumor suppressor gene have to be disrupted to abolish its function. The requested specificity for activating mutations in proto-oncogenes is high, since only a limited number of mutations at specific sites result in an activated protein. In contrast, disruption of a tumor suppressor gene can be accomplished via various mechanisms. Familial cancers often contain a germline mutation in one allele of a tumor suppressor gene. In tumors, the second allele is then frequently lost by genetic alterations that also affect the heterozygous state of multiple loci adjacent to the tumor suppressor gene. Genetic events especially, such as mitotic recombination, chromosome loss and deletion, are frequently responsible for the loss of the functional allele of heterozygous mutant tumor suppressor genes. We generated an Aprt(+/-) mouse model that allows us to study in detail the nature of the alterations that lead to loss of the wild-type Aprt allele in somatic cells. These genetic changes are thought to be analogous to those occurring at autosomal tumour suppressor genes, where they may contribute to the development of cancer. Furthermore, this mouse model allows determination of the extent and mechanisms by which chemical carcinogens induce loss of heterozygosity and identification of the nature of the DNA adducts responsible.
Copyright 1999 Wiley-Liss, Inc.