A cell-based model system links chromothripsis with hyperploidy

Balca R Mardin; Alexandros P Drainas; Sebastian M Waszak; Joachim Weischenfeldt; Mayumi Isokane; Adrian M Stütz; Benjamin Raeder; Theocharis Efthymiopoulos; Christopher Buccitelli; Maia Segura-Wang; Paul Northcott; Stefan M Pfister; Peter Lichter; Jan Ellenberg; Jan O Korbel

A cell-based model system links chromothripsis with hyperploidy

Balca R Mardin, Alexandros P Drainas, Sebastian M Waszak, Joachim Weischenfeldt, Mayumi Isokane, Adrian M Stütz, Benjamin Raeder, Theocharis Efthymiopoulos, Christopher Buccitelli, Maia Segura-Wang, Paul Northcott, Stefan M Pfister, Peter Lichter, Jan Ellenberg, Jan O Korbel

75 Citations (Scopus)

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.

Original language	English
Journal	Molecular Systems Biology
Volume	11
Issue number	9
Pages (from-to)	828
ISSN	1744-4292
Publication status	Published - 1 Sept 2015

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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.",

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T1 - A cell-based model system links chromothripsis with hyperploidy

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 M

AU - Lichter, Peter

AU - Ellenberg, Jan

AU - Korbel, Jan O

PY - 2015/9/1

Y1 - 2015/9/1

N2 - 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.

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.

M3 - Journal article

C2 - 26415501

SN - 1744-4292

VL - 11

SP - 828

JO - Molecular Systems Biology

JF - Molecular Systems Biology

IS - 9

ER -

A cell-based model system links chromothripsis with hyperploidy

Abstract

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