Abstract LB-032: A rat knockout of p53 that exhibits high rates of osteosarcoma and menigial sarcoma with frequent metastasis

Abstract

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 or have genetic limitations. 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 rat to create the F344-Tp53tm1(EGFP-Pac)QlyRrrc 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 Fischer 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. The inbred F344-Tp53tm1(EGFP-Pac)QlyRrrc knockout rat is a powerful model to investigate compelling questions surrounding the development of osteosarcomas and meningeal sarcomas. The inbred genetic background allows for easy maintenance of the model and introgression of additional mutations that already exist on the F344 background. We crossed the F344-Tp53tm1(EGFP-Pac)QlyRrrc rats to the F344-ApcPirc rat strain to examine the effects on tumor development. Tp53; Pirc double heterozygotes showed no difference in colonic or overall intestinal tumor number. Homozygous Tp53 heterozygous for the Pirc allele exhibited early onset pancreatic adenocarcinoma and rhabdomyosarcoma. There was also a significant absence of female homozygous Tp53 knockouts regardless of Apc status. Importantly, the rapid onset of osteosarcomas in the F344-Tp53tm1(EGFP-Pac)QlyRrrc fills a current void in animal models that recapitulate human pediatric osteosarcomas and may facilitate studies to identify therapeutic targets. Citation Format: James Amos-Landgraf, Sarah Hansen, Marcia Hart, Susheel Busi, Kevin Jones, Elizabeth Bryda. A rat knockout of p53 that exhibits high rates of osteosarcoma and menigial sarcoma with frequent metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-032.