2. Academic Validation
  3. Deep CRISPR mutagenesis characterizes the functional diversity of TP53 mutations

Deep CRISPR mutagenesis characterizes the functional diversity of TP53 mutations

  • Nat Genet. 2025 Jan;57(1):140-153. doi: 10.1038/s41588-024-02039-4.
Julianne S Funk 1,  Maria Klimovich 1,  Daniel Drangenstein 1,  Ole Pielhoop 1,  Pascal Hunold 1,  Anna Borowek 1,  Maxim Noeparast 1,  Evangelos Pavlakis 1,  Michelle Neumann 1,  Dimitrios-Ilias Balourdas 2 3,  Katharina Kochhan 1,  Nastasja Merle 1,  Imke Bullwinkel 1,  Michael Wanzel 1,  Sabrina Elmshäuser 1,  Julia Teply-Szymanski 4,  Andrea Nist 5,  Tara Procida 6,  Marek Bartkuhn 6 7,  Katharina Humpert 1 8,  Marco Mernberger 1,  Rajkumar Savai 6 9 10 11,  Thierry Soussi 12 13,  Andreas C Joerger 2 3,  Thorsten Stiewe 14 15 16 17 18
Affiliations

Affiliations

  • 1 Institute of Molecular Oncology, Philipps-University, Marburg, Germany.
  • 2 Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt am Main, Germany.
  • 3 Buchmann Institute for Molecular Life Sciences and Structural Genomics Consortium (SGC), Frankfurt am Main, Germany.
  • 4 Institute of Pathology, Philipps-University, Marburg University Hospital, Marburg, Germany.
  • 5 Genomics Core Facility, Philipps-University, Marburg, Germany.
  • 6 Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany.
  • 7 Biomedical Informatics and Systems Medicine, Justus-Liebig-University, Giessen, Germany.
  • 8 Bioinformatics Core Facility, Philipps-University, Marburg, Germany.
  • 9 Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Giessen, Germany.
  • 10 Cardio-Pulmonary Institute (CPI), Giessen, Germany.
  • 11 Lung Microenvironmental Niche in Cancerogenesis, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
  • 12 Centre de Recherche Saint-Antoine UMRS_938, INSERM, Sorbonne Université, Paris, France.
  • 13 Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Clinical Genetics, Uppsala University Hospital, Uppsala, Sweden.
  • 14 Institute of Molecular Oncology, Philipps-University, Marburg, Germany. stiewe@uni-marburg.de.
  • 15 Genomics Core Facility, Philipps-University, Marburg, Germany. stiewe@uni-marburg.de.
  • 16 Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany. stiewe@uni-marburg.de.
  • 17 Bioinformatics Core Facility, Philipps-University, Marburg, Germany. stiewe@uni-marburg.de.
  • 18 Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Giessen, Germany. stiewe@uni-marburg.de.
PMID: 39774325 DOI: 10.1038/s41588-024-02039-4
Abstract

The mutational landscape of TP53, a tumor suppressor mutated in about half of all cancers, includes over 2,000 known missense mutations. To fully leverage TP53 mutation status for personalized medicine, a thorough understanding of the functional diversity of these mutations is essential. We conducted a deep mutational scan using saturation genome editing with CRISPR-mediated homology-directed repair to engineer 9,225 TP53 variants in Cancer cells. This high-resolution approach, covering 94.5% of all cancer-associated TP53 missense mutations, precisely mapped the impact of individual mutations on tumor cell fitness, surpassing previous deep mutational scan studies in distinguishing benign from pathogenic variants. Our results revealed even subtle loss-of-function phenotypes and identified promising mutants for pharmacological reactivation. Moreover, we uncovered the roles of splicing alterations and nonsense-mediated messenger RNA decay in mutation-driven TP53 dysfunction. These findings underscore the power of saturation genome editing in advancing clinical TP53 variant interpretation for genetic counseling and personalized Cancer therapy.

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