Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations

Tobias Rausch; David T W Jones; Marc Zapatka; Adrian M Stütz; Thomas Zichner; Joachim Weischenfeldt; Natalie Jäger; Marc Remke; David Shih; Paul A Northcott; Elke Pfaff; Jelena Tica; Qi Wang; Luca Massimi; Hendrik Witt; Sebastian Bender; Sabrina Pleier; Huriye Cin; Cynthia Hawkins; Christian Beck; Andreas von Deimling; Volkmar Hans; Benedikt Brors; Roland Eils; Wolfram Scheurlen; Jonathon Blake; Vladimir Benes; Andreas E Kulozik; Olaf Witt; Dianna Martin; Cindy Zhang; Rinnat Porat; Diana M Merino; Jonathan Wasserman; Nada Jabado; Adam Fontebasso; Lars Bullinger; Frank G Rücker; Konstanze Döhner; Hartmut Döhner; Jan Koster; Jan J Molenaar; Rogier Versteeg; Marcel Kool; Uri Tabori; David Malkin; Andrey Korshunov; Michael D Taylor; Peter Lichter; Stefan M Pfister; Jan O Korbel

doi:10.1016/j.cell.2011.12.013

Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations

Tobias Rausch, David T W Jones, Marc Zapatka, Adrian M Stütz, Thomas Zichner, Joachim Weischenfeldt, Natalie Jäger, Marc Remke, David Shih, Paul A Northcott, Elke Pfaff, Jelena Tica, Qi Wang, Luca Massimi, Hendrik Witt, Sebastian Bender, Sabrina Pleier, Huriye Cin, Cynthia Hawkins, Christian BeckAndreas von Deimling, Volkmar Hans, Benedikt Brors, Roland Eils, Wolfram Scheurlen, Jonathon Blake, Vladimir Benes, Andreas E Kulozik, Olaf Witt, Dianna Martin, Cindy Zhang, Rinnat Porat, Diana M Merino, Jonathan Wasserman, Nada Jabado, Adam Fontebasso, Lars Bullinger, Frank G Rücker, Konstanze Döhner, Hartmut Döhner, Jan Koster, Jan J Molenaar, Rogier Versteeg, Marcel Kool, Uri Tabori, David Malkin, Andrey Korshunov, Michael D Taylor, Peter Lichter, Stefan M Pfister, Jan O Korbel

532 Citations (Scopus)

Abstract

Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer.

Original language	English
Journal	Cell
Volume	148
Issue number	1-2
Pages (from-to)	59-71
Number of pages	13
ISSN	0092-8674
DOIs	https://doi.org/10.1016/j.cell.2011.12.013
Publication status	Published - 20 Jan 2012
Externally published	Yes

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Rausch, T., Jones, D. T. W., Zapatka, M., Stütz, A. M., Zichner, T., Weischenfeldt, J., Jäger, N., Remke, M., Shih, D., Northcott, P. A., Pfaff, E., Tica, J., Wang, Q., Massimi, L., Witt, H., Bender, S., Pleier, S., Cin, H., Hawkins, C., ... Korbel, J. O. (2012). Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell, 148(1-2), 59-71. https://doi.org/10.1016/j.cell.2011.12.013

Rausch, T, Jones, DTW, Zapatka, M, Stütz, AM, Zichner, T, Weischenfeldt, J, Jäger, N, Remke, M, Shih, D, Northcott, PA, Pfaff, E, Tica, J, Wang, Q, Massimi, L, Witt, H, Bender, S, Pleier, S, Cin, H, Hawkins, C, Beck, C, von Deimling, A, Hans, V, Brors, B, Eils, R, Scheurlen, W, Blake, J, Benes, V, Kulozik, AE, Witt, O, Martin, D, Zhang, C, Porat, R, Merino, DM, Wasserman, J, Jabado, N, Fontebasso, A, Bullinger, L, Rücker, FG, Döhner, K, Döhner, H, Koster, J, Molenaar, JJ, Versteeg, R, Kool, M, Tabori, U, Malkin, D, Korshunov, A, Taylor, MD, Lichter, P, Pfister, SM & Korbel, JO 2012, 'Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations', Cell, vol. 148, no. 1-2, pp. 59-71. https://doi.org/10.1016/j.cell.2011.12.013

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title = "Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations",

abstract = "Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer.",

keywords = "Animals, Brain Neoplasms, Child, Chromosome Aberrations, DNA Copy Number Variations, DNA Mutational Analysis, Disease Models, Animal, Gene Rearrangement, Humans, Leukemia, Myeloid, Acute, Li-Fraumeni Syndrome, Medulloblastoma, Mice, Middle Aged, Tumor Suppressor Protein p53",

author = "Tobias Rausch and Jones, {David T W} and Marc Zapatka and St{\"u}tz, {Adrian M} and Thomas Zichner and Joachim Weischenfeldt and Natalie J{\"a}ger and Marc Remke and David Shih and Northcott, {Paul A} and Elke Pfaff and Jelena Tica and Qi Wang and Luca Massimi and Hendrik Witt and Sebastian Bender and Sabrina Pleier and Huriye Cin and Cynthia Hawkins and Christian Beck and {von Deimling}, Andreas and Volkmar Hans and Benedikt Brors and Roland Eils and Wolfram Scheurlen and Jonathon Blake and Vladimir Benes and Kulozik, {Andreas E} and Olaf Witt and Dianna Martin and Cindy Zhang and Rinnat Porat and Merino, {Diana M} and Jonathan Wasserman and Nada Jabado and Adam Fontebasso and Lars Bullinger and R{\"u}cker, {Frank G} and Konstanze D{\"o}hner and Hartmut D{\"o}hner and Jan Koster and Molenaar, {Jan J} and Rogier Versteeg and Marcel Kool and Uri Tabori and David Malkin and Andrey Korshunov and Taylor, {Michael D} and Peter Lichter and Pfister, {Stefan M} and Korbel, {Jan O}",

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AU - Rausch, Tobias

AU - Jones, David T W

AU - Zapatka, Marc

AU - Stütz, Adrian M

AU - Zichner, Thomas

AU - Weischenfeldt, Joachim

AU - Jäger, Natalie

AU - Remke, Marc

AU - Shih, David

AU - Northcott, Paul A

AU - Pfaff, Elke

AU - Tica, Jelena

AU - Wang, Qi

AU - Massimi, Luca

AU - Witt, Hendrik

AU - Bender, Sebastian

AU - Pleier, Sabrina

AU - Cin, Huriye

AU - Hawkins, Cynthia

AU - Beck, Christian

AU - von Deimling, Andreas

AU - Hans, Volkmar

AU - Brors, Benedikt

AU - Eils, Roland

AU - Scheurlen, Wolfram

AU - Blake, Jonathon

AU - Benes, Vladimir

AU - Kulozik, Andreas E

AU - Witt, Olaf

AU - Martin, Dianna

AU - Zhang, Cindy

AU - Porat, Rinnat

AU - Merino, Diana M

AU - Wasserman, Jonathan

AU - Jabado, Nada

AU - Fontebasso, Adam

AU - Bullinger, Lars

AU - Rücker, Frank G

AU - Döhner, Konstanze

AU - Döhner, Hartmut

AU - Koster, Jan

AU - Molenaar, Jan J

AU - Versteeg, Rogier

AU - Kool, Marcel

AU - Tabori, Uri

AU - Malkin, David

AU - Korshunov, Andrey

AU - Taylor, Michael D

AU - Lichter, Peter

AU - Pfister, Stefan M

AU - Korbel, Jan O

PY - 2012/1/20

Y1 - 2012/1/20

N2 - Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer.

AB - Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer.

KW - Animals

KW - Brain Neoplasms

KW - Child

KW - Chromosome Aberrations

KW - DNA Copy Number Variations

KW - DNA Mutational Analysis

KW - Disease Models, Animal

KW - Gene Rearrangement

KW - Humans

KW - Leukemia, Myeloid, Acute

KW - Li-Fraumeni Syndrome

KW - Medulloblastoma

KW - Mice

KW - Middle Aged

KW - Tumor Suppressor Protein p53

U2 - 10.1016/j.cell.2011.12.013

DO - 10.1016/j.cell.2011.12.013

M3 - Journal article

C2 - 22265402

SN - 0092-8674

VL - 148

SP - 59

EP - 71

JO - Cell

JF - Cell

IS - 1-2

ER -

Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations

Abstract

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