Multi-omic and single-cell profiling of chromothriptic medulloblastoma reveals genomic and transcriptomic consequences of genome instability

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 () and Aurélie Ernst ()
Additional contact information
Petr Smirnov: German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
Moritz J. Przybilla: Genome Biology Unit
Milena Simovic-Lorenz: German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
R. Gonzalo Parra: Genome Biology Unit
Hana Susak: Genome Biology Unit
Manasi Ratnaparkhe: German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
John KL. Wong: German Cancer Research Center (DKFZ)
Verena Körber: German Cancer Research Center (DKFZ)
Jan-Philipp Mallm: German Cancer Research Center (DKFZ) and Bioquant
George Philippos: German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
Martin Sill: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Thorsten Kolb: German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
Rithu Kumar: German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
Nicola Casiraghi: Genome Biology Unit
Konstantin Okonechnikov: Hopp Children’s Cancer Center Heidelberg (KiTZ)
David R. Ghasemi: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Kendra Korinna Maaß: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Kristian W. Pajtler: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Anna Jauch: Heidelberg University
Andrey Korshunov: Heidelberg University Hospital
Thomas Höfer: German Cancer Research Center (DKFZ)
Marc Zapatka: German Cancer Research Center (DKFZ)
Stefan M. Pfister: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Wolfgang Huber: Genome Biology Unit
Oliver Stegle: Genome Biology Unit
Aurélie Ernst: German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54547-w

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