The Evolution of Tumor Formation in Humans and Mice with Inherited Mutations in the P53 Gene

While tumors are very heterogeneous in their origins, mutations in the p53 gene and inactivation of p53 gene functions are the most common feature that predispose to the formation of cancers in humans. Inherited p53 mutations lead to different tumor types at very different frequencies and at very different ages than somatic p53 mutations. The reasons for this are explored. When the first mutation arises in a stem cell (a gatekeeper mutation) it selects for a specific subset of second mutations which in turn select for mutations in a third subset of genes. The nature of the first mutation in a tumor determines, by selection, the functional types of subsequent mutations. Inherited mutations occur at different developmental times and in different orders of mutational sequences than somatic mutations. The excess risk of developing a cancer with an inherited p53 mutation is two- to three-fold in endodermal derived tissues compared with 100- to 1000-fold for ectodermal and mesenchymal derived tissues. By contrast, endodermal derived tumors with somatic p53 mutations occur at very high frequencies (70-100%). These evolutionary restrictions upon the mutational path that tumor development may take could open up new avenues for therapy and prevention.