title: Fischer-344 Tp53-knockout rats exhibit a high rate of bone and brain neoplasia with frequent metastasis.
abstract: Somatic mutations in the Tp53 tumor suppressor gene are the most commonly seen genetic alterations in cancer, and germline mutations in Tp53 predispose individuals to a variety of early-onset cancers. Development of appropriate translational animal models that carry mutations in Tp53 and recapitulate human disease are important for drug discovery, biomarker development and disease modeling. Current Tp53 mouse and rat models have significant phenotypic and genetic limitations, and often do not recapitulate certain aspects of human disease. We used a marker-assisted speed congenic approach to transfer a well-characterized Tp53-mutant allele from an outbred rat to the genetically inbred Fischer-344 (F344) rat to create the F344-Tp53tm1(EGFP-Pac)Qly/Rrrc (F344-Tp53) strain. On the F344 genetic background, the tumor spectrum shifted, with the primary tumor types being osteosarcomas and meningeal sarcomas, compared to the hepatic hemangiosarcoma and lymphoma identified in the original outbred stock model. The Fischer model is more consistent with the early onset of bone and central nervous system sarcomas found in humans with germline Tp53 mutations. The frequency of osteosarcomas in F344-Tp53 homozygous and heterozygous animals was 57% and 36%, respectively. Tumors were highly representative of human disease radiographically and histologically, with tumors found primarily on long bones with frequent pulmonary metastases. Importantly, the rapid onset of osteosarcomas in this promising new model fills a current void in animal models that recapitulate human pediatric osteosarcomas and could facilitate studies to identify therapeutic targets.
authors.affiliation: Department of Veterinary Pathobiology, University of Missouri, Columbia, MI 65211, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Hansen
authors.affiliation: Department of Veterinary Pathobiology, University of Missouri, Columbia, MI 65211, USA.
authors.forename: Marcia L
authors.initials: ML
authors.lastname: Hart
authors.affiliation: Department of Veterinary Pathobiology, University of Missouri, Columbia, MI 65211, USA.
authors.forename: Susheel
authors.initials: S
authors.lastname: Busi
authors.affiliation: Department of Veterinary Pathobiology, University of Missouri, Columbia, MI 65211, USA.
authors.forename: Taybor
authors.initials: T
authors.lastname: Parker
authors.affiliation: Rat Resource and Research Center, University of Missouri, Columbia, MI 65211, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Goerndt
authors.affiliation: Departments of Orthopaedics and Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Kevin
authors.identifier: 0000-0003-1531-2157
authors.initials: K
authors.lastname: Jones
authors.affiliation: Department of Veterinary Pathobiology, University of Missouri, Columbia, MI 65211, USA Rat Resource and Research Center, University of Missouri, Columbia, MI 65211, USA brydae@missouri.edu amoslandgrafj@missouri.edu.
authors.forename: James M
authors.identifier: 0000-0003-2535-7746
authors.initials: JM
authors.lastname: Amos-Landgraf
authors.affiliation: Department of Veterinary Pathobiology, University of Missouri, Columbia, MI 65211, USA Rat Resource and Research Center, University of Missouri, Columbia, MI 65211, USA brydae@missouri.edu amoslandgrafj@missouri.edu.
authors.forename: Elizabeth C
authors.identifier: 0000-0002-9936-3607
authors.initials: EC
authors.lastname: Bryda
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000473:pathology*; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D008175:Lung Neoplasms / Q000556:secondary; D008577:Meningeal Neoplasms / Q000473:pathology; D009154:Mutation / Q000235:genetics; D009362:Neoplasm Metastasis; D012516:Osteosarcoma / Q000000981:diagnostic imaging / Q000473:pathology; D010641:Phenotype; D011916:Rats, Inbred F344; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53
keywords: Cancer; Osteosarcoma; Rat; Sarcoma; p53