A cell‐based model system links chromothripsis with hyperploidy. Issue 9 (September 2015)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Molecular systems biology. Volume 11:Issue 9(2015:Sep.)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2015-09
• Subjects: Molecular biology -- Periodicals; Systems biology -- Periodicals; 572.8
• DOI: 10.15252/msb.20156505
• Languages: English
• ISSNs: 1744-4292

Abstract

<abstract abstract-type="main" id="msb156505-abs-0001"> <title>Abstract</title> <p>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 <italic>in vitro</italic> 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 <italic>in vitro</italic> 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 <italic>in vivo</italic>. CAST provides the foundation for mechanistic dissection of complex DNA rearrangement processes.</p> </abstract>