tp53R217H and R242H Mutant Zebrafish Exhibit Dysfunctional p53 Hallmarks and Recapitulate Li-Fraumeni Syndrome Phenotypes

Abstract

AbstractLi-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with a highly penetrant cancer spectrum characterized by germlineTP53mutations. We characterized the first LFS zebrafish hotspot mutants,tp53R217H and R242H (human R248H and R273H), and found these mutants exhibit partial-to-no activation of p53 target genes, have a defective G1 cell-cycle checkpoint, and are resistant to apoptosis. Spontaneous tumor development histologically resembling human sarcomas developed as early as 6 months.tp53R242H mutants had a higher lifetime tumor incidence compared totp53null and R217H mutants, suggesting it is a more aggressive mutation. We observed mutation-specific tumor phenotypes acrosstp53mutants with associated diverse transcriptomic and DNA methylome profiles, impacting metabolism, cell signalling, and biomacromolecule synthesis and degradation. Thesetp53zebrafish mutants demonstrate fidelity to their human counterparts and provide new insights into underlying tumorigenesis mechanisms and kinetics, which will guide targeted therapeutics for LFS.