Defining function of wild-type and 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 TP53 effects on tumorigenesis remains central to realizing better treatment outcomes. In ERMS, >70% of patients retain wild-type TP53 , yet TP53 mutations when present in tumors are associated with poor prognosis. Employing a kRAS ^G12D -driven ERMS tumor model and newly generated tp53 null (tp53 ^-/- ) zebrafish, we define both wild-type and patient-specific TP53 mutant effects on tumorigenesis. We demonstrate that tp53 is a major suppressor of tumor initiation, where tp53 loss expands tumors initiation from <35% to >97% of animals. Next, characterizing three patient-specific mutants finds that TP53 ^C176F partially retains wild-type p53 apoptotic activity that can be exploited, while the TP53 ^P153Δ and TP53 ^Y220C mutants define two structural mutations that predispose to head musculature ERMS.