Multi-omic and single-cell profiling of chromothriptic medulloblastoma reveals genomic and transcriptomic consequences of genome instability
Abstract 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 tumou...
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54547-w |
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| author | Petr Smirnov Moritz J. Przybilla Milena Simovic-Lorenz R. Gonzalo Parra Hana Susak Manasi Ratnaparkhe John KL. Wong Verena Körber Jan-Philipp Mallm George Philippos Martin Sill Thorsten Kolb Rithu Kumar Nicola Casiraghi Konstantin Okonechnikov David R. Ghasemi Kendra Korinna Maaß Kristian W. Pajtler Anna Jauch Andrey Korshunov Thomas Höfer Marc Zapatka Stefan M. Pfister Wolfgang Huber Oliver Stegle Aurélie Ernst |
| author_facet | Petr Smirnov Moritz J. Przybilla Milena Simovic-Lorenz R. Gonzalo Parra Hana Susak Manasi Ratnaparkhe John KL. Wong Verena Körber Jan-Philipp Mallm George Philippos Martin Sill Thorsten Kolb Rithu Kumar Nicola Casiraghi Konstantin Okonechnikov David R. Ghasemi Kendra Korinna Maaß Kristian W. Pajtler Anna Jauch Andrey Korshunov Thomas Höfer Marc Zapatka Stefan M. Pfister Wolfgang Huber Oliver Stegle Aurélie Ernst |
| author_sort | Petr Smirnov |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-b45147ed89fa4fafa213cbfffa64258f |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b45147ed89fa4fafa213cbfffa64258f2025-02-02T12:30:57ZengNature PortfolioNature Communications2041-17232024-11-0115112010.1038/s41467-024-54547-wMulti-omic and single-cell profiling of chromothriptic medulloblastoma reveals genomic and transcriptomic consequences of genome instabilityPetr Smirnov0Moritz J. Przybilla1Milena Simovic-Lorenz2R. Gonzalo Parra3Hana Susak4Manasi Ratnaparkhe5John KL. Wong6Verena Körber7Jan-Philipp Mallm8George Philippos9Martin Sill10Thorsten Kolb11Rithu Kumar12Nicola Casiraghi13Konstantin Okonechnikov14David R. Ghasemi15Kendra Korinna Maaß16Kristian W. Pajtler17Anna Jauch18Andrey Korshunov19Thomas Höfer20Marc Zapatka21Stefan M. Pfister22Wolfgang Huber23Oliver Stegle24Aurélie Ernst25Group Genome Instability in Tumors, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)European Molecular Biology Laboratory, Genome Biology UnitGroup Genome Instability in Tumors, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)European Molecular Biology Laboratory, Genome Biology UnitEuropean Molecular Biology Laboratory, Genome Biology UnitGroup Genome Instability in Tumors, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)Division of Molecular Genetics, German Cancer Research Center (DKFZ)Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ)Single-cell Open Lab, German Cancer Research Center (DKFZ) and BioquantGroup Genome Instability in Tumors, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)Hopp Children’s Cancer Center Heidelberg (KiTZ)Group Genome Instability in Tumors, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)Group Genome Instability in Tumors, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)European Molecular Biology Laboratory, Genome Biology UnitHopp Children’s Cancer Center Heidelberg (KiTZ)Hopp Children’s Cancer Center Heidelberg (KiTZ)Hopp Children’s Cancer Center Heidelberg (KiTZ)Hopp Children’s Cancer Center Heidelberg (KiTZ)Institute of Human Genetics, Heidelberg UniversityClinical Cooperation Unit Neuropathology, DKFZ, Department of Neuropathology, Heidelberg University HospitalDivision of Theoretical Systems Biology, German Cancer Research Center (DKFZ)Division of Molecular Genetics, German Cancer Research Center (DKFZ)Hopp Children’s Cancer Center Heidelberg (KiTZ)European Molecular Biology Laboratory, Genome Biology UnitEuropean Molecular Biology Laboratory, Genome Biology UnitGroup Genome Instability in Tumors, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)Abstract 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.https://doi.org/10.1038/s41467-024-54547-w |
| spellingShingle | Petr Smirnov Moritz J. Przybilla Milena Simovic-Lorenz R. Gonzalo Parra Hana Susak Manasi Ratnaparkhe John KL. Wong Verena Körber Jan-Philipp Mallm George Philippos Martin Sill Thorsten Kolb Rithu Kumar Nicola Casiraghi Konstantin Okonechnikov David R. Ghasemi Kendra Korinna Maaß Kristian W. Pajtler Anna Jauch Andrey Korshunov Thomas Höfer Marc Zapatka Stefan M. Pfister Wolfgang Huber Oliver Stegle Aurélie Ernst Multi-omic and single-cell profiling of chromothriptic medulloblastoma reveals genomic and transcriptomic consequences of genome instability Nature Communications |
| title | Multi-omic and single-cell profiling of chromothriptic medulloblastoma reveals genomic and transcriptomic consequences of genome instability |
| title_full | Multi-omic and single-cell profiling of chromothriptic medulloblastoma reveals genomic and transcriptomic consequences of genome instability |
| title_fullStr | Multi-omic and single-cell profiling of chromothriptic medulloblastoma reveals genomic and transcriptomic consequences of genome instability |
| title_full_unstemmed | Multi-omic and single-cell profiling of chromothriptic medulloblastoma reveals genomic and transcriptomic consequences of genome instability |
| title_short | Multi-omic and single-cell profiling of chromothriptic medulloblastoma reveals genomic and transcriptomic consequences of genome instability |
| title_sort | multi omic and single cell profiling of chromothriptic medulloblastoma reveals genomic and transcriptomic consequences of genome instability |
| url | https://doi.org/10.1038/s41467-024-54547-w |
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