STOCHASTIC MODELING OF TUMORIGENESIS IN P53 DEFICIENT MICE

Stochastic models of tumorigenesis have been developed to investigate the implications of experimental data on tumour induction in wild-type and p53-deficient mice for tumorigenesis mechanisms. Conventional mul tistage models in which inactivation of each p53 allele represents a d istinct stage predict excessively large numbers of tumours in p53-defi cient genotypes, allowing this category of model to be rejected. Multi stage multipath models, in which a p53-mediated pathway co-exists with one or more p53-independent pathways, are consistent with the data, a lthough these models require unknown pathways and do not enable age-sp ecific curves of tumour appearance to be computed. An alternative mode l that fits the data is the 'multigate' model in which tumorigenesis r esults from a small number of gate-pass (enabling) events independentl y of p53 status. The role of p53 inactivation is as a rate modifier th at accelerates the gate-pass events. This model implies that wild-type p53 acts as a 'caretaker' to maintain genetic uniformity in cell popu lations, and that p53 inactivation increases the probability of occurr ence of a viable cellular mutant by a factor of about ten. The multiga te model predicts a relationship between the time pattern of tumour oc currence and tumour genotype that should be experimentally testable. S tochastic modelling may help to distinguish 'gatekeeper' and 'caretake r' genes in other tumorigenic pathays.