Reduced latency but no increased brain tumor penetrance in mice with astrocyte specific expression of a human p53 mutant

p53-germline mutations located in the core DNA-binding domain have been ass ociated with a more dominant tumor penetrance especially for breast cancer and brain tumors. We previously reported an unusual accumulation of CNS tur ners associated with a unique p53 germline mutation, Y236 Delta (deletion o f codon 236). To test whether this tissue-specific tumor predisposition ref lects a gain-of-function activity of Y236 Delta, we generated transgenic mi ce expressing Y236 Delta in astrocytes using the regulatory elements of the glial fibrillary acidic protein (G-FAP) gene. After transplacental exposur e to N-ethyl-N-nitrosourea (25mg/kg BW) brain tumors developed in 18% (7/39 ) of GFAP-Y236 Delta transgenic p53(+/-) mice, while in p53(+/-) mice the i ncidence was 28% (11/40) (P > 0.3). However, the mean tumor latency for GFA P-Y236 Delta /p53(+/-) mice was significantly shorter than for p53(+/-) mic e, with 19.9 weeks vs 31.6 weeks (P = 0.039), respectively. Taken together, cell specific expression of Y236 Delta results in an acceleration of tumor progression but does not confer a higher tumor penetrance. Conceivably, th e transdominant effect of Y236 Delta provided a growth advantage early in t he progression of neoplastic cells, since the endogenous p53 wild-type alle le was lost in all brain tumors independent of the genotype. This reflects well observations from human astrocytic neoplasms with p53 mutations.