Oncogenic and teratogenic effects of Trp53Y217C, an inflammation-prone mouse model of the human hotspot mutant TP53Y220C

Abstract Missense “hotspot” mutations localized in six p53 codons account for 20% of TP53 mutations 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 generated Trp53Y217C, a mouse model of the human hotspot mutant TP53Y220C. DNA damage responses were lost in Trp53Y217C/Y217C cells, and Trp53Y217C/Y217C fibroblasts exhibited increased chromosome instability compared to Trp53-/- cells. Furthermore, Trp53Y217C/Y217C male mice died earlier than Trp53-/- males, with more aggressive thymic lymphomas. This correlated with an increased expression of inflammation-related genes in Trp53Y217C/Y217C thymic cells compared to Trp53-/- cells. Surprisingly, we recovered only one Trp53Y217C/Y217C female for 22 Trp53Y217C/Y217C males at weaning, a skewed distribution explained by a high frequency of Trp53Y217C/Y217C female embryos with exencephaly and the death of most Trp53Y217C/Y217C female 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 viable Trp53Y217C/Y217C weaned females in their progeny. Together, these data suggest that the p53Y217C mutation not only abrogates wildtype p53 functions but also promotes inflammation, with oncogenic effects in males and teratogenic effects in females.