TY  - JOUR
AU  - Mardin, Balca R
AU  - Drainas, Alexandros P
AU  - Waszak, Sebastian M
AU  - Weischenfeldt, Joachim
AU  - Isokane, Mayumi
AU  - Stütz, Adrian M
AU  - Raeder, Benjamin
AU  - Efthymiopoulos, Theocharis
AU  - Buccitelli, Christopher
AU  - Segura-Wang, Maia
AU  - Northcott, Paul
AU  - Pfister, Stefan
AU  - Lichter, Peter
AU  - Ellenberg, Jan
AU  - Korbel, Jan O
TI  - A cell-based model system links chromothripsis with hyperploidy.
JO  - Molecular systems biology
VL  - 11
IS  - 9
SN  - 1744-4292
CY  - Heidelberg
PB  - EMBO Press
M1  - DKFZ-2017-03090
SP  - 828
PY  - 2015
AB  - 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.
KW  - Telomeric Repeat Binding Protein 2 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:26415501
C2  - pmc:PMC4592670
UR  - https://inrepo02.dkfz.de/record/127064
ER  -