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.
authors.affiliation: European Molecular Biology Laboratory, Meyerhofstr. 1, 69117 Heidelberg, Germany.
authors.forename: Tobias
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authors.lastname: Rausch
authors.forename: David T W
authors.initials: DT
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authors.forename: Adrian M
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authors.forename: Huriye
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authors.forename: Volkmar
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authors.forename: Wolfram
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authors.lastname: Blake
authors.forename: Vladimir
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authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kulozik
authors.forename: Olaf
authors.initials: O
authors.lastname: Witt
authors.forename: Dianna
authors.initials: D
authors.lastname: Martin
authors.forename: Cindy
authors.initials: C
authors.lastname: Zhang
authors.forename: Rinnat
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authors.lastname: Porat
authors.forename: Diana M
authors.initials: DM
authors.lastname: Merino
authors.forename: Jonathan
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authors.lastname: Wasserman
authors.forename: Nada
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authors.lastname: Jabado
authors.forename: Adam
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authors.lastname: Fontebasso
authors.forename: Lars
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authors.lastname: Bullinger
authors.forename: Frank G
authors.initials: FG
authors.lastname: Rücker
authors.forename: Konstanze
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authors.lastname: Döhner
authors.forename: Hartmut
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authors.lastname: Döhner
authors.forename: Jan
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authors.lastname: Koster
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Molenaar
authors.forename: Rogier
authors.initials: R
authors.lastname: Versteeg
authors.forename: Marcel
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authors.lastname: Kool
authors.forename: Uri
authors.initials: U
authors.lastname: Tabori
authors.forename: David
authors.initials: D
authors.lastname: Malkin
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.forename: Jan O
authors.initials: JO
authors.lastname: Korbel
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics*; D002648:Child; D002869:Chromosome Aberrations; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D015321:Gene Rearrangement; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D016864:Li-Fraumeni Syndrome / Q000503:physiopathology; D008527:Medulloblastoma / Q000235:genetics*; D051379:Mice; D008875:Middle Aged; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53