Defining function of wild-type and three patient-specific TP53 mutations in a zebrafish model of embryonal rhabdomyosarcoma

In embryonal rhabdomyosarcoma (ERMS) and generally in sarcomas, the role of wild-type and loss- or gain-of-function TP53 mutations remains largely undefined. Eliminating mutant or restoring wild-type p53 is challenging; nevertheless, understanding p53 variant effects on tumorigenesis remains central to realizing better treatment outcomes. In ERMS, >70% of patients retain wild-type TP53, yet mutations when present are associated with worse prognosis. Employing a kRAS(G12D)-driven ERMS tumor model and tp53 null (tp53(-/-)) zebrafish, we define wild-type and patient-specific TP53 mutant effects on tumorigenesis. We demonstrate that tp53 is a major suppressor of tumorigenesis, where tp53 loss expands tumor initiation from <35% to >97% of animals. Characterizing three patient-specific alleles reveals that TP53(C176F) partially retains wild-type p53 apoptotic activity that can be exploited, whereas TP53(P153Δ) and TP53(Y220C) encode two structurally related proteins with gain-of-function effects that predispose to head musculature ERMS. TP53(P153Δ) unexpectedly also predisposes to hedgehog-expressing medulloblastomas in the kRAS(G12D)-driven ERMS-model.