title: A cell-based model system links chromothripsis with hyperploidy.
abstract: 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.
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
authors.forename: Balca R
authors.initials: BR
authors.lastname: Mardin
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
authors.forename: Alexandros P
authors.initials: AP
authors.lastname: Drainas
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
authors.forename: Sebastian M
authors.initials: SM
authors.lastname: Waszak
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Weischenfeldt
authors.affiliation: European Molecular Biology Laboratory, Cell Biology and Biophysics Unit, Heidelberg, Germany.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Isokane
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Stütz
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Raeder
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
authors.forename: Theocharis
authors.initials: T
authors.lastname: Efthymiopoulos
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Buccitelli
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
authors.forename: Maia
authors.initials: M
authors.lastname: Segura-Wang
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Northcott
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.affiliation: European Molecular Biology Laboratory, Cell Biology and Biophysics Unit, Heidelberg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Ellenberg
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany korbel@embl.de.
authors.forename: Jan O
authors.initials: JO
authors.lastname: Korbel
mesh_terms: D000782:Aneuploidy; D002455:Cell Division; D002460:Cell Line; D002869:Chromosome Aberrations; D002877:Chromosomes, Human / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D015321:Gene Rearrangement; D015894:Genome, Human / Q000235:genetics*; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*; D011123:Polyploidy; D016615:Telomere / Q000235:genetics / Q000473:pathology; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics / Q000378:metabolism
chemical_list: D035341:Telomeric Repeat Binding Protein 2
keywords: DNA rearrangements; chromothripsis; hyperploidy; telomere damage; transformation