Grant: Doctoral Research Award : Priority Announcement - Primary Prevention of Cancer

Li-Fraumeni Syndrome (LFS) is an inherited disorder typically caused by mutations in the TP53 gene in every cell of the body. These mutations greatly increase the risk of developing cancer, usually during childhood. p53, the protein product of the TP53 gene, normally functions as a genome guardian, preventing tumours from developing by helping repair damage to DNA or by inducing damaged cells to die before they can divide and acquire additional cancer-causing mutations. In the majority of patients with LFS, TP53 is mutated such that it is no longer protective and may actually have new cancer-causing properties. LFS patients develop a variety of tumour types, often much earlier in life than those without inherited TP53 mutations. Animal models representing the different mutations observed in LFS offer the promise of explaining how these tumours develop and provide a platform for testing molecularly targeted therapies. The zebrafish is a useful tool to model LFS as it is surprisingly very genetically similar to humans and contains many of the same organs and tissues, which develop cancers that resemble their human counterparts. Furthermore, the external fertilization of zebrafish eggs allows easy access for genetic manipulation. To investigate how TP53 mutations impact tumour development, we have created two zebrafish lines that contain common LFS tp53 mutations. Our LFS zebrafish mutants recapitulate what is observed in other LFS model systems (mice and cell culture), as well as what is observed in LFS patients, as they are resistant to stress-induced cell death and develop tumours. We have observed differences in tumour growth between our two tp53 mutants, such as anatomic location, time to onset, lifetime incidence and sex ratios. My goal is to utilize these zebrafish mutants to shed light on the different mechanisms driving tumour development in LFS and assess prospective therapeutic compounds as potential anti-cancer agents that may prevent cancer development.