Somatic mutations in the TP53 tumor suppressor gene are one of the most commonly observed genetic alterations in cancer, and germline mutations in TP53 result in Li-Fraumeni syndrome and predispose individuals to a variety of early-onset cancers. Current Tp53 mouse and rat models have significant phenotypic and genetic limitations and often do not recapitulate the certain aspects of human disease. The majority of Tp53 rat mutants are maintained as outbred stocks, potentially contributing to the variability of the phenotypes. We used a marker-assisted speed congenic approach to transfer a well-characterized Tp53 mutant allele from an outbred Sprague Dawley (SD) rat stock to the genetically inbred Fischer 344 (F344) rat to create the F344-Tp53tm1(EGFP-Pac)Qly/Rrrc rat strain. On the F344 genetic background the tumor spectrum shifted, with the primary tumor types being osteosarcomas (32%) and meningeal sarcomas (32%), compared to the hepatic hemangiosarcoma (80% incidence in homozygotes) and lymphoma (55% incidence in heterozygotes) identified in the original outbred stock model. The F344 model is more consistent with the early onset of bone and central nervous system sarcomas found in humans with germline TP53 mutations. Osteosarcomas represented 36% and 31% of tumors that developed, in homozygous and heterozygous animals, respectively, and were highly representative of the human disease radiographically and histologically, with tumors harbored primarily on long bones with frequent pulmonary metastases.
We crossed the F344-Tp53tm1(EGFP-Pac)Qly/Rrrc knockout rat to the F344/NTac-ApcPirc model of familial colon cancer to determine the effect on intestinal and extracolonic cancer development. There was no significant change in tumor multiplicities between any of the genotypic classes; however, there was a reduced number of Tp53 homozygous mutants than expected and no female homozygous mutants were recovered.
The F344-Tp53tm1(EGFP-Pac)Qly/Rrrc knockout rat is a powerful model to investigate compelling questions surrounding the development of osteosarcomas and meningeal sarcomas in the context of an inbred genetic background allowing for easy maintenance of the model and introgression of additional mutations that already exist in other strains on the F344 background. Importantly, the rapid onset of osteosarcomas and the unique lammellar bone structure in the rat compared to mice fills a current void in animal models that recapitulate human pediatric osteosarcomas and may facilitate studies to identify therapeutic targets.