A cell-based model system links chromothripsis with hyperploidy
| Autor: | Mardin, Balca R, Drainas, Alexandros P, Waszak, Sebastian M, Weischenfeldt, Joachim, Isokane, Mayumi, Stütz, Adrian M, Raeder, Benjamin, Efthymiopoulos, Theocharis, Buccitelli, Christopher, Segura‐Wang, Maia, Northcott, Paul, Pfister, Stefan M, Lichter, Peter, Ellenberg, Jan, Korbel, Jan O |
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| Rok vydání: | 2015 |
| Předmět: |
Genome instability
DNA Copy Number Variations hyperploidy Computational biology Biology Genome telomere damage General Biochemistry Genetics and Molecular Biology Genomic Instability Cell Line Polyploidy Neoplasms Chromosomes Human Humans Telomeric Repeat Binding Protein 2 Genetics Chromosome Aberrations Gene Rearrangement Chromothripsis Massive parallel sequencing General Immunology and Microbiology Genome Human Applied Mathematics transformation Gene rearrangement Articles Telomere Aneuploidy DNA rearrangements Computational Theory and Mathematics chromothripsis Human genome General Agricultural and Biological Sciences Hyperploidy Cell Division Information Systems Medulloblastoma |
| Zdroj: | Molecular Systems Biology |
| ISSN: | 1744-4292 |
| Popis: | A remarkable observation emerging from recent cancer genome analyses is the identification of chromothripsis as a one-off genomic catastrophe, resulting in massive somatic DNA structural rearrangements (SRs). Largely due to lack of suitable model systems, the mechanistic basis of chromothripsis has remained elusive. We developed an integrative method termed "complex alterations after selection and transformation (CAST)," enabling efficient in vitro generation of complex DNA rearrangements including chromothripsis, using cell perturbations coupled with a strong selection barrier followed by massively parallel sequencing. We employed this methodology to characterize catastrophic SR formation processes, their temporal sequence, and their impact on gene expression and cell division. Our in vitro system uncovered a propensity of chromothripsis to occur in cells with damaged telomeres, and in particular in hyperploid cells. Analysis of primary medulloblastoma cancer genomes verified the link between hyperploidy and chromothripsis in vivo. CAST provides the foundation for mechanistic dissection of complex DNA rearrangement processes. |
| Databáze: | OpenAIRE |
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