RGD Reference Report - Fischer-344 Tp53-knockout rats exhibit a high rate of bone and brain neoplasia with frequent metastasis. - Rat Genome Database

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Fischer-344 Tp53-knockout rats exhibit a high rate of bone and brain neoplasia with frequent metastasis.

Authors: Hansen, Sarah A  Hart, Marcia L  Busi, Susheel  Parker, Taybor  Goerndt, Angela  Jones, Kevin  Amos-Landgraf, James M  Bryda, Elizabeth C 
Citation: Hansen SA, etal., Dis Model Mech. 2016 Oct 1;9(10):1139-1146. Epub 2016 Aug 15.
RGD ID: 12738450
Pubmed: PMID:27528400   (View Abstract at PubMed)
PMCID: PMC5087826   (View Article at PubMed Central)
DOI: DOI:10.1242/dmm.025767   (Journal Full-text)

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-Tp53(tm1(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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
meninges sarcoma  IMP 12738450; 12738450 RGD 
osteosarcoma  IMP 12738450; 12738450 RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
premature death  IMP 12738450; 12738450 RGD 
Objects Annotated

Genes (Rattus norvegicus)
Tp53  (tumor protein p53)

Additional Information