Mice carrying nonsense mutant p53 develop spontaneous tumors with frequent metastases

The TP53 tumor suppressor gene is mutated in a large fraction of human tumors. Close to 11% of TP53 mutations are nonsense mutations, causing premature termination of protein synthesis and expression of truncated inactive p53 protein. The most common TP53 nonsense mutation in human cancer is R213X. To study the impact of TP53 nonsense mutations in vivo , we generated mice harboring the Trp53 nonsense mutation R210X that corresponds to human TP53 R213X. Initially, Trp53 ^R210X mice appear phenotypically normal, although the proportion of female Trp53 ^R210X/R210X mice is dramatically reduced. Female homozygous mice are poor breeders and remain smaller and lighter than female heterozygous and wildtype littermates. Trp53 ^R210X/R210X mice start to show tumors at 2.5 months of age, and their maximal lifespan is 8.5 months. Trp53 ^R210X/+ mice present tumors from 9 months of age, and by 16.5 months of age 50% of all heterozygous mice have developed overt tumors. 70% of tumors from Trp53 ^R210X/+ mice show loss of heterozygosity (LOH). The most common tumor type in homozygous mice is T-cell lymphoma, while soft-tissue sarcoma and osteosarcoma are the predominant tumor types in heterozygous mice. Although the Trp53 ^R210X tumor phenotype is comparable to those of Trp53 -null and Trp53 -missense knock-in mice, Trp53 ^R210X/R210X mice develop frequent metastases and Trp53 ^R210X/+ mice have a longer overall survival than Trp53 ^R172H/+ missense mutant knock-in mice. Treatment of T-cell lymphoma cells from Trp53 ^R210X/R210X mice with aminoglycoside G418 induces translational readthrough and expression of full-length functional p53. Our new unique mouse model will allow further studies of the effects of Trp53 nonsense mutation in a multi-organ system and serve as a model for the Li-Fraumeni syndrome (LFS). It will also be valuable for preclinical evaluation of novel therapeutic strategies for targeting TP53 nonsense mutations in cancer.