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

Medientyp: E-Artikel

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

Beteiligte: Rausch, Tobias [VerfasserIn]; Remke, Marc [VerfasserIn]; Wang, Qi [VerfasserIn]; Witt, Hendrik [VerfasserIn]; Bender, Sebastian [VerfasserIn]; Pleier, Sabrina Valesca [VerfasserIn]; Beck, Christian [VerfasserIn]; Deimling, Andreas von [VerfasserIn]; Eils, Roland [VerfasserIn]; Kulozik, Andreas [VerfasserIn]; Witt, Olaf [VerfasserIn]; Korshunov, Andrey [VerfasserIn]; Pfister, Stefan [VerfasserIn]

Erschienen: 19 January 2012

Sprache: Englisch

DOI: 10.1016/j.cell.2011.12.013

ISSN: 1097-4172

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Beschreibung: Summary 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.

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