Oncogenic and teratogenic effects ofTrp53^Y217C, an inflammation-prone mouse model of the human hotspot mutantTP53^Y220C

Missense “hotspot” mutations localized in six p53 codons account for 20% ofTP53mutations in human cancers. Hotspot p53 mutants have lost the tumor suppressive functions of the wildtype protein, but whether and how they may gain additional functions promoting tumorigenesis remain controversial. Here we generatedTrp53^Y217C, a mouse model of the human hotspot mutantTP53^Y220C. DNA damage responses were lost inTrp53^Y217C/Y217Ccells, andTrp53^Y217C/Y217Cfibroblasts exhibited increased chromosome instability compared toTrp53^-/-cells. Furthermore,Trp53^Y217C/Y217Cmale mice died earlier thanTrp53^-/-males, with more aggressive thymic lymphomas. This correlated with an increased expression of inflammation-related genes inTrp53^Y217C/Y217Cthymic cells compared toTrp53^-/-cells. Surprisingly, we recovered only oneTrp53^Y217C/Y217Cfemale for 22Trp53^Y217C/Y217Cmales at weaning, a skewed distribution explained by a high frequency ofTrp53^Y217C/Y217Cfemale embryos with exencephaly and the death of mostTrp53^Y217C/Y217Cfemale neonates. Strikingly however, when we treated pregnant females with the anti-inflammatory drug supformin (LCC-12) we observed a five-fold increase in the proportion of viableTrp53^Y217C/Y217Cweaned females in their progeny. Together, these data suggest that the p53^Y217Cmutation not only abrogates wildtype p53 functions but also promotes inflammation, with oncogenic effects in males and teratogenic effects in females.