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

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  • 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
Vis graf over relationer

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
Eksternt udgivetJa

ID: 55087137