Novel p53 mutants selected in BRCA-associated tumours which dissociate transformation suppression from other wild-type p53 functions

Inheritance of germ-line mutant alleles of BRCA1 and BRCA2 confers a marked ly increased risk of breast cancer and we have previously reported a higher incidence of p53 mutations in these tumours than in grade matched sporadic tumours, We have now characterized these p53 mutants, The results of these studies identify a novel class of p53 mutants previously undescribed in hu man cancer Set with multiple occurrences in BRCA-associated tumours which r etain a profile of p53-dependent activities in terms of transactivation, gr owth suppression and apoptosis induction which is close or equal to wild-ty pe. However, these mutants fail to suppress transformation and exhibit gain of function transforming activity in rat embryo fibroblasts, These mutants therefore fall into a novel category of p53 mutants which dissociate trans formation suppression from other wild-type functions. The rarity of these m utants in human cancer and their multiple occurrence in BRCA-associated bre ast tumours suggests that these novel p53 mutants are selected during malig nant progression in the unique genetic background of BRCA1- and BRCA2-assoc iated tumours.