Defining function of wild-type and three patient-specific <i>TP53</i> mutations in a zebrafish model of embryonal rhabdomyosarcoma.

Abstract

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