Abstract 672: Differential effects of p53 mutations on cancer invasion and metastasis in a mouse model of colon cancer

Abstract

Abstract Inactivation of the APC (adenomatous polyposis coli) tumor suppressor gene plays an important role in initiating most adenomas and colorectal cancers (CRCs). Somatic mutations in the TP53 tumor suppressor gene and KRAS oncogene are found in roughly 60% and 40% of CRCs, respectively, and contribute to tumor progression. In the vast majority of human CRCs, TP53 missense mutations lead to high levels of mutant p53 protein expression and the loss of the other wild type TP53 allele. To evaluate the role of TP53 missense mutations in CRC progression, we generated a genetically engineered mouse model of colorectal carcinoma, via combined targeting of Apc, Kras, and Trp53 alleles in mouse colon epithelium, focusing on comparing phenotypic effects of the murine equivalent of the human R273H mutation (i.e., murine R270H mutation) or a large deletion mutation of mouse Trp53. Inactivation of one allele Apc and activation of an oncogenic Kras allele in colon epithelium generated serrated and hyperplastic morphologic epithelium and adenomas. The addition of either the R270H missense mutation or the Trp53 null mutation to the Apc and Kras mutations led to markedly shortened survival of the mice, due to the development of multiple colon tumors in each mouse ranging from adenomas to late stage adenocarcinomas. Evidence of invasion into the smooth muscle and serosa area was found in both compound mice with missense or deletion mutations in Trp53, with the Trp53R270H mutant mice displaying an increased prevalence of deeply invasive tumors relative to the mice with deletion of Trp53. Furthermore, we found that the missense mutant Trp53R270H allele in combination with Apc and Kras mutations, but not the null-mutant Trp53 allele, was strongly linked to metastases to lymph nodes and lung. We have developed a useful mouse model of metastatic colon cancer that recapitulates the role of TP53 mutations in cooperating with APC and KRAS mutations in human CRC development and progression. In addition, our findings strongly suggest a powerful role for missense mutant p53 proteins compared to TP53 null mutations in promoting invasion and metastasis in CRC progression. Citation Format: Ying Feng, Naoya Sakamoto, Maranne Green, Megan Greenn, Kathleen R. Cho, Eric R. Fearon. Differential effects of p53 mutations on cancer invasion and metastasis in a mouse model of colon cancer. [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 672.