1. Single cell multi-omics analysis of chromothriptic medulloblastoma highlights genomic and transcriptomic consequences of genome instability
- Author
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Manasi Ratnaparkhe, Thomas Hoefer, Kendra K. Maass, Martin Sill, Anna Jauch, Oliver Stegle, Przybilla Mj, Thorsten Kolb, Marc Zapatka, David R Ghasemi, John Wong, Andrey Korshunov, Aurélie Ernst, Koerber, Kristian W. Pajtler, Rajesh Kumar, Nicola Casiraghi, Stefan M. Pfister, Hana Susak, Parra Rg, Mallm P, and Milena Simovic
- Subjects
Genome instability ,Medulloblastoma ,Genetics ,Transcriptome ,medicine.anatomical_structure ,Chromothripsis ,Somatic cell ,Cell ,medicine ,Multi omics ,Chromosome ,Biology ,medicine.disease - Abstract
Chromothripsis is a form of genome instability, whereby a presumably single catastrophic event generates extensive genomic rearrangements of one or few chromosome(s). However, little is known about the heterogeneity of chromothripsis across different clones from the same tumor, as well as changes in response to treatment. We analyzed single-cell genomic and transcriptomic alterations linked with chromothripsis in human p53-deficient medulloblastoma (n=7). We reconstructed the order of somatic events, identified early alterations likely linked to chromothripsis and depicted the contribution of chromothripsis to malignancy. We characterized subclonal variation of chromothripsis and its effects on double-minute chromosomes, cancer drivers and putatively druggable targets. Furthermore, we highlighted the causative role and the fitness consequences of specific rearrangements in neural progenitors.Graphical Abstract
- Published
- 2021