{"doi":"10.7554/elife.68221","title":"Defining function of wild-type and three patient-specific TP53 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 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.","journal":"eLife","year":2023,"id":370148,"datarank":0.3582972346329204,"base_score":2.0794415416798357,"endowment":2.0794415416798357,"self_citation_contribution":0.31191623125197543,"citation_network_contribution":0.046381003380945,"self_endowment_contribution":0.31191623125197543,"citer_contribution":0.046381003380945,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":5,"citers_with_citation_signal":4,"citers_with_endowment":4,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9606,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE213869"],"Dryad":["10.5061/dryad.zgmsbccb6"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":679629,"name":"Kunal Baxi","orcid":"0000-0001-6094-6410","position":1,"is_corresponding":false},{"id":825689,"name":"Amanda Lipsitt","orcid":"0000-0002-3757-8493","position":2,"is_corresponding":false},{"id":679630,"name":"Nicole R. 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