tp53 R217H and R242H mutant zebrafish exhibit dysfunctional p53 hallmarks and recapitulate Li-Fraumeni syndrome phenotypes

Kim Kobar; Lissandra Tuzi; Jennifer A Fiene; Erin Burnley; Kristianne J C Galpin; Craig Midgen; Brianne Laverty; Vallijah Subasri; Timmy T Wen; Martin Hirst; Michelle Moksa; Annaick Carles; Qi Cao; Adam Shlien; David Malkin; Sergey V Prykhozhij; Jason N Berman

doi:10.1016/j.bbadis.2024.167612

tp53 R217H and R242H mutant zebrafish exhibit dysfunctional p53 hallmarks and recapitulate Li-Fraumeni syndrome phenotypes

Biochim Biophys Acta Mol Basis Dis. 2024 Dec 4;1871(3):167612. doi: 10.1016/j.bbadis.2024.167612. Online ahead of print.

Authors

Kim Kobar¹, Lissandra Tuzi¹, Jennifer A Fiene¹, Erin Burnley², Kristianne J C Galpin³, Craig Midgen⁴, Brianne Laverty⁵, Vallijah Subasri⁶, Timmy T Wen⁷, Martin Hirst⁸, Michelle Moksa⁹, Annaick Carles⁹, Qi Cao⁹, Adam Shlien⁷, David Malkin¹⁰, Sergey V Prykhozhij³, Jason N Berman¹¹

Affiliations

¹ Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
² Translational and Molecular Medicine Program, University of Ottawa, Ottawa, ON, Canada.
³ Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
⁴ Department of Pathology, IWK Health Centre, Halifax, NS, Canada.
⁵ Genetics and Genome Biology Program, Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Canada.
⁶ Genetics and Genome Biology Program, Hospital for Sick Children, Toronto, ON, Canada; Peter Munk Cardiac Center, University Health Network, Toronto, ON, Canada.
⁷ Genetics and Genome Biology Program, Hospital for Sick Children, Toronto, ON, Canada; Laboratory of Medicine and Pathobiology, University of Toronto, Canada.
⁸ Department of Microbiology and Immunology, Michael Smith Laboratories, UBC, Vancouver, Canada; Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, Canada.
⁹ Department of Microbiology and Immunology, Michael Smith Laboratories, UBC, Vancouver, Canada.
¹⁰ Genetics and Genome Biology Program, Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Canada; Department of Pediatrics, Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada.
¹¹ Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada; Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada. Electronic address: jberman@cheo.on.ca.

PMID: 39643218
DOI: 10.1016/j.bbadis.2024.167612

Abstract

Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with a highly penetrant cancer spectrum characterized by germline TP53 mutations. We characterized the first LFS zebrafish hotspot mutants, tp53 R217H and R242H (human R248H and R273H), and found these mutants exhibit partial-to-no activation of p53 target genes, have defective cell-cycle checkpoints, and display partial-to-full resistance to apoptosis, although the R217H mutation has hypomorphic characteristics. Spontaneous tumor development histologically resembling human sarcomas was observed as early as 6 months. tp53 R242H mutants had a higher lifetime tumor incidence compared to tp53 null and R217H mutants, suggesting it is a more aggressive mutation. We observed mutation-specific tumor phenotypes across tp53 mutants with associated diverse transcriptomic and DNA methylome profiles in tp53 mutant larvae, impacting metabolism, cell signalling, and biomacromolecule synthesis and degradation. These tp53 zebrafish mutants demonstrate fidelity to their human counterparts and provide new insights into underlying tumorigenesis mechanisms and kinetics that suggest metabolic rewiring and cellular signalling changes occur prior to tumor initiation, which will guide targeted therapeutics for LFS.

Keywords: Cancer; Cancer predisposition; Li-Fraumeni syndrome; Zebrafish; p53; tp53.