Abstract LB-258: The human Aurora-A kinase Phe31Ile polymorphism affects cancer susceptibility in a knock-in mouse model.

Abstract

Abstract Aurora-A kinase is a serine/threonine kinase that is essential for faithful chromosome segregation during mitosis. A single nucleotide polymorphism T91A (amino acid Phe31→Ile) present in the coding region of human Aurora-A is associated with susceptibility to multiple cancer types, yet the precise biochemical mechanisms by which these different polymorphisms function are still not well characterized. To investigate the functional differences between the two alleles of Aurora-A, we have generated a knock-in mouse that carries the human-specific Aurora-A Phe31 allele. Normally, rodents only carry the Ile allele. Homozygous (F/F) and heterozygous (F/I) mice for this knock-in allele were born healthy and fertile with no obvious phenotype. Growth rates of MEFs isolated from F/F, F/I, and I/I embryos showed no significant differences. To investigate the oncogenic properties of each variant in tumor development in the context of different p53 status, we generated a series of Aurora-A knock-in/p53-deficient double mutant mice. All mice were exposed to a single dose of 4Gy whole-body γ-radiation at 5 weeks of age and observed daily until they were moribund, then sacrificed and autopsied. While the I/I genotype conferred increased risk (reduced latency) compared to the F/F genotype in the p53+/- mice (p=0.037), the reverse was observed in the p53-/- mice (p=0.009); 43% of the I/I mice versus 25% of the F/F mice developed lymphomas in the p53+/- background, while 55% of the I/I mice versus 76% of the F/F mice developed lymphomas in the p53-/- background. These results support our hypothesis that the two polymorphisms confer differential susceptibility to lymphoma development in a p53-dependent manner. Interestingly, Aurora-A+/- heterozygous null mice (F/- and I/- on the p53+/- background) showed increased incidence and decreased latency of tumor formation compared to the Aurora-A+/+ mice. These data suggest dual roles for Aurora-A as both an oncogene and a haploinsufficient tumor suppressor in lymphomagenesis. There exist complex regulatory mechanisms between Aurora-A and p53, emphasizing that a balanced level of Aurora-A is critical for cell survival and maintenance of genome integrity. These data highlight the critical role of interactions between common inherited genetic variants in determining tumor susceptibility, a phenomenon that may underlie the “Missing heritability” noted in GWAS in human populations. Citation Format: Ihn Young Song, Atul Kumar, Reyno Delrosario, Jian-Hua Mao, Allan Balmain. The human Aurora-A kinase Phe31Ile polymorphism affects cancer susceptibility in a knock-in mouse model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-258. doi:10.1158/1538-7445.AM2013-LB-258