Genetic and stochastic influences upon tumor formation and tumor types in Li-Fraumeni mouse models.

is the most frequently mutated gene in human cancers. Li-Fraumeni syndrome patients inheriting heterozygous mutations often have a much-increased risk to develop cancer(s) at early ages. Recent studies suggest that some individuals inherited mutations do not have the early onset or high frequency of cancers. These observations suggest that other genetic, environmental, immunological, epigenetic, or stochastic factors modify the penetrance of the cancerous mutant Tp53 phenotype. To test this possibility, this study explored dominant genetic modifiers of mutations in heterozygous mice with different genetic backgrounds. Both genetic and stochastic effects upon tumor formation were observed in these mice. The genetic background of mice carrying mutations has a strong influence upon the tissue type of the tumor produced and the number of tumors formed in a single mouse. The onset age of a tumor is correlated with the tissue type of that tumor, although identical tumor tissue types can occur at very different ages. These observations help to explain the great diversity of cancers in different Li-Fraumeni patients over lifetimes.