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

*Corresponding author af dette arbejde
700 Citationer (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.

OriginalsprogEngelsk
TidsskriftCell
Vol/bind148
Udgave nummer1-2
Sider (fra-til)59-71
Antal sider13
ISSN0092-8674
DOI
StatusUdgivet - 20 jan. 2012
Udgivet eksterntJa

Fingeraftryk

Dyk ned i forskningsemnerne om 'Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations'. Sammen danner de et unikt fingeraftryk.

Citationsformater