Using the zebrafish as a model for chemoprevention for TP53 mutation carriers

Patients with Li Fraumeni syndrome (LFS) have a mutation in a gene called TP53 in every cell in their bodies, which puts them at much greater risk for developing cancers early in life and throughout their lifetime. While surveillance programs that include MRIs and other imaging tests have helped identify these tumours earlier so that they are more easily treated, these patients still require intensive therapy to cure their cancers. Patients who survive their first tumour are likely to have second, third and more tumours that will all need treatment. What types of cancer and when these tumours will develop is hard to predict. Drs. Malkin and Shlien have been studying a large number of LFS patients and have identified the most common specific mutations in TP53, the history of cancers in these patients and the secondary mutations that may contribute to cancer development. It would be ideal to be able to predict based on genetics, which patients are at risk for developing which cancers and provide a treatment that restores normal TP53 levels to prevent the cancer from forming. In order to determine if the findings from patients are predictive and to test potential treatments, animal models are needed. The zebrafish shares similar genetics to humans, fertilizes externally producing large numbers of offspring, which are transparent and easily studied. We have already genetically engineered zebrafish to contain the most common TP53 mutations found in LFS and these fish develop cancers by 8-10 months of age. We can screen these fish early in development for signs that their TP53 gene is not functional and introduce additional mutations found in LFS patient tumours. We can then use these young fish to screen for drugs that restore normal TP53 and observe if cancers are prevented. By demonstrating that these responses in zebrafish are conserved in patient samples, we aim to improve the outcome for these children.