Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder that causes cancer in humans. Patients present with a wide variety of tumor types, including sarcomas, at an early age. The tumor suppressor protein p53 is mutated in 60% of LFS patients and in 70% of sporadic cancers, indicating the importance of p53 in preventing tumorigenesis. The identification of genes, other than p53, that contribute to LFS has been inhibited by the small size of LFS families with a normal p53 gene; in addition, some LFS families with particular p53 mutations have an increased cancer predisposition, suggesting that some p53 mutations may have additional activities beyond loss of function. Model organisms can be manipulated quickly and easily to help understand both the variable effects of p53 mutations and the contributions of other mutated proteins to cancer predisposition, and may accelerate the development of new treatment options for LFS.

Here, the authors demonstrate conserved p53 signaling in zebrafish, a vertebrate model system that is amenable to rapid genetic and pharmacological screens. Chemically mutagenized fish were screened for p53 mutants, which were defective in a p53-dependent irradiation-induced apoptotic response. Affected fish recapitulated many of the LFS phenotypes, including the onset of sarcomas in heterozygotes owing to loss of heterozygosity (LOH). Multiple experimental approaches show that the mutated p53 allele has activities beyond loss of function, including the ability to inhibit the non-mutant allele in a dominant-negative fashion. These data show that zebrafish are a valid and useful system in which to study LFS.

This study demonstrates the potential of zebrafish to model autosomal dominant human cancer predispositions and LOH, a crucial mechanism in many human cancers, using LFS as an exemplar. Further experiments using the zebrafish LFS mutant should help to elucidate the mechanism by which p53 dominant-negative activity occurs. Future genetic modifier screens will search for novel genes that are important in cancer progression through several mechanisms, including synergistic tumor induction, modulation of p53 protein stability, altered genome instability and LOH. The p53 zebrafish mutants should provide a foundation for small molecule screens to identify compounds that specifically kill p53 mutant cells in vivo.

2010