Open AccessA cell‐based model system links chromothripsis with hyperploidy
Author(s) -
Mardin Balca R,
Drainas Alexandros P,
Waszak Sebastian M,
Weischenfeldt Joachim,
Isokane Mayumi,
Stütz Adrian M,
Raeder Benjamin,
Efthymiopoulos Theocharis,
Buccitelli Christopher,
SeguraWang Maia,
Northcott Paul,
Pfister Stefan M,
Lichter Peter,
Ellenberg Jan,
Korbel Jan O
Publication year - 2015
Publication title -
molecular systems biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.523
H-Index - 148
ISSN - 1744-4292
DOI - 10.15252/msb.20156505
Subject(s) - chromothripsis , biology , computational biology , genetics , microbiology and biotechnology , cell , cancer research , genome instability , dna , dna damage
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 ( SR s). 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.