The landscape of chromothripsis across adult cancer types

Natalia Voronina; John K.L. Wong; Daniel Hübschmann; Mario Hlevnjak; Sebastian Uhrig; Christoph E. Heilig; Peter Horak; Simon Kreutzfeldt; Andreas Mock; Albrecht Stenzinger; Barbara Hutter; Martina Fröhlich; Benedikt Brors; Arne Jahn; Barbara Klink; Laura Gieldon; Lina Sieverling; Lars Feuerbach; Priya Chudasama; Katja Beck; Matthias Kroiss; Christoph Heining; Lino Möhrmann; Andrea Fischer; Evelin Schröck; Hanno Glimm; Marc Zapatka; Peter Lichter; Stefan Fröhling; Aurélie Ernst

doi:10.1038/s41467-020-16134-7

The landscape of chromothripsis across adult cancer types

Natalia Voronina, John K.L. Wong, Daniel Hübschmann, Mario Hlevnjak, Sebastian Uhrig, Christoph E. Heilig, Peter Horak, Simon Kreutzfeldt, Andreas Mock, Albrecht Stenzinger, Barbara Hutter, Martina Fröhlich, Benedikt Brors, Arne Jahn, Barbara Klink, Laura Gieldon, Lina Sieverling, Lars Feuerbach, Priya Chudasama, Katja BeckMatthias Kroiss, Christoph Heining, Lino Möhrmann, Andrea Fischer, Evelin Schröck, Hanno Glimm, Marc Zapatka, Peter Lichter, Stefan Fröhling, Aurélie Ernst^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Research › peer-review

45 Citations (Scopus)

Abstract

Chromothripsis is a recently identified mutational phenomenon, by which a presumably single catastrophic event generates extensive genomic rearrangements of one or a few chromosome(s). Considered as an early event in tumour development, this form of genome instability plays a prominent role in tumour onset. Chromothripsis prevalence might have been underestimated when using low-resolution methods, and pan-cancer studies based on sequencing are rare. Here we analyse chromothripsis in 28 tumour types covering all major adult cancers (634 tumours, 316 whole-genome and 318 whole-exome sequences). We show that chromothripsis affects a substantial proportion of human cancers, with a prevalence of 49% across all cases. Chromothripsis generates entity-specific genomic alterations driving tumour development, including clinically relevant druggable fusions. Chromothripsis is linked with specific telomere patterns and univocal mutational signatures in distinct tumour entities. Longitudinal analysis of chromothriptic patterns in 24 matched tumour pairs reveals insights in the clonal evolution of tumours with chromothripsis.

Original language	English
Article number	2320
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16134-7
Publication status	Published - 1 Dec 2020
Externally published	Yes

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Voronina, N., Wong, J. K. L., Hübschmann, D., Hlevnjak, M., Uhrig, S., Heilig, C. E., Horak, P., Kreutzfeldt, S., Mock, A., Stenzinger, A., Hutter, B., Fröhlich, M., Brors, B., Jahn, A., Klink, B., Gieldon, L., Sieverling, L., Feuerbach, L., Chudasama, P., ... Ernst, A. (2020). The landscape of chromothripsis across adult cancer types. Nature Communications, 11(1), [2320]. https://doi.org/10.1038/s41467-020-16134-7

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title = "The landscape of chromothripsis across adult cancer types",

abstract = "Chromothripsis is a recently identified mutational phenomenon, by which a presumably single catastrophic event generates extensive genomic rearrangements of one or a few chromosome(s). Considered as an early event in tumour development, this form of genome instability plays a prominent role in tumour onset. Chromothripsis prevalence might have been underestimated when using low-resolution methods, and pan-cancer studies based on sequencing are rare. Here we analyse chromothripsis in 28 tumour types covering all major adult cancers (634 tumours, 316 whole-genome and 318 whole-exome sequences). We show that chromothripsis affects a substantial proportion of human cancers, with a prevalence of 49% across all cases. Chromothripsis generates entity-specific genomic alterations driving tumour development, including clinically relevant druggable fusions. Chromothripsis is linked with specific telomere patterns and univocal mutational signatures in distinct tumour entities. Longitudinal analysis of chromothriptic patterns in 24 matched tumour pairs reveals insights in the clonal evolution of tumours with chromothripsis.",

author = "Natalia Voronina and Wong, {John K.L.} and Daniel H{\"u}bschmann and Mario Hlevnjak and Sebastian Uhrig and Heilig, {Christoph E.} and Peter Horak and Simon Kreutzfeldt and Andreas Mock and Albrecht Stenzinger and Barbara Hutter and Martina Fr{\"o}hlich and Benedikt Brors and Arne Jahn and Barbara Klink and Laura Gieldon and Lina Sieverling and Lars Feuerbach and Priya Chudasama and Katja Beck and Matthias Kroiss and Christoph Heining and Lino M{\"o}hrmann and Andrea Fischer and Evelin Schr{\"o}ck and Hanno Glimm and Marc Zapatka and Peter Lichter and Stefan Fr{\"o}hling and Aur{\'e}lie Ernst",

note = "Funding Information: We thank the DKFZ Genomics Core facility for excellent support for the sequencing analyses, the DKFZ-Heidelberg Center for Personalized Oncology (DKFZ-HIPO, project number HIPO21) and the Else Kr{\"o}ner Fresenius Foundation, Fritz Thyssen foundation and Wilhelm Sander Foundation for funding. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

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doi = "10.1038/s41467-020-16134-7",

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Voronina, N, Wong, JKL, Hübschmann, D, Hlevnjak, M, Uhrig, S, Heilig, CE, Horak, P, Kreutzfeldt, S, Mock, A, Stenzinger, A, Hutter, B, Fröhlich, M, Brors, B, Jahn, A, Klink, B, Gieldon, L, Sieverling, L, Feuerbach, L, Chudasama, P, Beck, K, Kroiss, M, Heining, C, Möhrmann, L, Fischer, A, Schröck, E, Glimm, H, Zapatka, M, Lichter, P, Fröhling, S & Ernst, A 2020, 'The landscape of chromothripsis across adult cancer types', Nature Communications, vol. 11, no. 1, 2320. https://doi.org/10.1038/s41467-020-16134-7

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T1 - The landscape of chromothripsis across adult cancer types

AU - Voronina, Natalia

AU - Wong, John K.L.

AU - Hübschmann, Daniel

AU - Hlevnjak, Mario

AU - Uhrig, Sebastian

AU - Heilig, Christoph E.

AU - Horak, Peter

AU - Kreutzfeldt, Simon

AU - Mock, Andreas

AU - Stenzinger, Albrecht

AU - Hutter, Barbara

AU - Fröhlich, Martina

AU - Brors, Benedikt

AU - Jahn, Arne

AU - Klink, Barbara

AU - Gieldon, Laura

AU - Sieverling, Lina

AU - Feuerbach, Lars

AU - Chudasama, Priya

AU - Beck, Katja

AU - Kroiss, Matthias

AU - Heining, Christoph

AU - Möhrmann, Lino

AU - Fischer, Andrea

AU - Schröck, Evelin

AU - Glimm, Hanno

AU - Zapatka, Marc

AU - Lichter, Peter

AU - Fröhling, Stefan

AU - Ernst, Aurélie

N1 - Funding Information: We thank the DKFZ Genomics Core facility for excellent support for the sequencing analyses, the DKFZ-Heidelberg Center for Personalized Oncology (DKFZ-HIPO, project number HIPO21) and the Else Kröner Fresenius Foundation, Fritz Thyssen foundation and Wilhelm Sander Foundation for funding. Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Chromothripsis is a recently identified mutational phenomenon, by which a presumably single catastrophic event generates extensive genomic rearrangements of one or a few chromosome(s). Considered as an early event in tumour development, this form of genome instability plays a prominent role in tumour onset. Chromothripsis prevalence might have been underestimated when using low-resolution methods, and pan-cancer studies based on sequencing are rare. Here we analyse chromothripsis in 28 tumour types covering all major adult cancers (634 tumours, 316 whole-genome and 318 whole-exome sequences). We show that chromothripsis affects a substantial proportion of human cancers, with a prevalence of 49% across all cases. Chromothripsis generates entity-specific genomic alterations driving tumour development, including clinically relevant druggable fusions. Chromothripsis is linked with specific telomere patterns and univocal mutational signatures in distinct tumour entities. Longitudinal analysis of chromothriptic patterns in 24 matched tumour pairs reveals insights in the clonal evolution of tumours with chromothripsis.

AB - Chromothripsis is a recently identified mutational phenomenon, by which a presumably single catastrophic event generates extensive genomic rearrangements of one or a few chromosome(s). Considered as an early event in tumour development, this form of genome instability plays a prominent role in tumour onset. Chromothripsis prevalence might have been underestimated when using low-resolution methods, and pan-cancer studies based on sequencing are rare. Here we analyse chromothripsis in 28 tumour types covering all major adult cancers (634 tumours, 316 whole-genome and 318 whole-exome sequences). We show that chromothripsis affects a substantial proportion of human cancers, with a prevalence of 49% across all cases. Chromothripsis generates entity-specific genomic alterations driving tumour development, including clinically relevant druggable fusions. Chromothripsis is linked with specific telomere patterns and univocal mutational signatures in distinct tumour entities. Longitudinal analysis of chromothriptic patterns in 24 matched tumour pairs reveals insights in the clonal evolution of tumours with chromothripsis.

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DO - 10.1038/s41467-020-16134-7

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SN - 2041-1723

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JO - Nature Communications

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The landscape of chromothripsis across adult cancer types

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