Multi-omic and single-cell profiling of chromothriptic medulloblastoma reveals genomic and transcriptomic consequences of genome instability
Chromothripsis is a frequent form of genome instability, whereby a presumably single catastrophic event generates extensive genomic rearrangements of one or multiple chromosome(s). However, little is known about the heterogeneity of chromothripsis across different clones from the same tumour, as well as changes in response to treatment. Here we analyse single-cell genomic and transcriptomic alterations linked with chromothripsis in human p53-deficient medulloblastoma and neural stem cells (n = 9). We reconstruct the order of somatic events, identify early alterations likely linked to chromothripsis and depict the contribution of chromothripsis to malignancy. We characterise subclonal variation of chromothripsis and its effects on extrachromosomal circular DNA, cancer drivers and putatively druggable targets. Furthermore, we highlight the causative role and the fitness consequences of specific rearrangements in neural progenitors.
Authors
- Aurélie Ernst (ORCID: https://orcid.org/0000-0002-8082-3677)
- Kristian W. Pajtler (ORCID: https://orcid.org/0000-0002-3562-6121)
- Konstantin Okonechnikov (ORCID: https://orcid.org/0000-0002-3409-2340)
- Milena Simović (ORCID: https://orcid.org/0000-0001-8835-6885)
- Rithu Kumar
- Anna Jauch (ORCID: https://orcid.org/0000-0002-0771-3084)
- R. Gonzalo Parra (ORCID: https://orcid.org/0000-0003-2446-016X)
- Thomas Höfer (ORCID: https://orcid.org/0000-0003-3560-8780)
- Wolfgang K. Huber (ORCID: https://orcid.org/0000-0002-0474-2218)
- David R. Ghasemi (ORCID: https://orcid.org/0000-0002-3844-9933)
- Thorsten Kolb (ORCID: https://orcid.org/0000-0001-7663-2109)
- Andrey Korshunov (ORCID: https://orcid.org/0000-0002-5257-3623)
- Hana Sušak (ORCID: https://orcid.org/0000-0002-7965-7675)
- Stefan M. Pfister (ORCID: https://orcid.org/0000-0002-5447-5322)
- Marc Zapatka (ORCID: https://orcid.org/0000-0001-8287-5967)
- Jan‐Philipp Mallm (ORCID: https://orcid.org/0000-0002-7059-4030)
- Nicola Casiraghi (ORCID: https://orcid.org/0000-0002-5390-544X)
- Petr Smirnov (ORCID: https://orcid.org/0000-0001-9395-8450)
- John Wong (ORCID: https://orcid.org/0000-0001-6362-373X)
- Verena Körber (ORCID: https://orcid.org/0009-0005-3888-2648)
- Moritz Jakob Przybilla (ORCID: https://orcid.org/0000-0001-5645-9492)
- George Philippos (ORCID: https://orcid.org/0000-0002-8433-9719)
- Manasi Ratnaparkhe
- Kendra K. Maaß (ORCID: https://orcid.org/0000-0001-9357-5038)
- Martin Sill (ORCID: https://orcid.org/0000-0001-7616-7665)
- Oliver Stegle (ORCID: https://orcid.org/0000-0002-8818-7193)
Institutions
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- Barcelona Supercomputing Center (ES)
- University Hospital Heidelberg (DE)
- Wellcome Sanger Institute (GB)
- Hopp Children's Cancer Center Heidelberg (DE)
- European Molecular Biology Laboratory (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Universitat Politècnica de Catalunya (ES)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-23
- DOI
- https://doi.org/10.1038/s41467-024-54547-w
- Citations
- 10
- Primary Topic
- Cancer Genomics and Diagnostics
- Type
- article
- Field-Weighted Citation Impact
- 2.85
Funders
- Deutsches Krebsforschungszentrum
- Wilhelm Sander-Stiftung
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Fritz Thyssen Stiftung
- Studienstiftung des Deutschen Volkes
- Deutsche Krebshilfe
- Deutsche Kinderkrebsstiftung
- Instituto de Salud Carlos III