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 P153D and TP53 Y220C encode two structurally related proteins with gain-of-function effects that predispose to head musculature ERMS. TP53 P153D unexpectedly also predisposes to hedgehog expressing medulloblastomas in the kRAS G12D -driven ERMS-model.