Journal
CELL
Volume 148, Issue 1-2, Pages 59-71Publisher
CELL PRESS
DOI: 10.1016/j.cell.2011.12.013
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Funding
- German Cancer Aid [109252]
- BMBF [01GS0871]
- European Commission [Health-F2-2010-260791]
- NIH [R01CA148699b]
- Pediatric Brain Tumor Foundation
- Canadian Institutes for Health Research [MOP-97834]
- German Research Foundation [BU 1339/3-1, KO 4037/1-1]
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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 acutemyeloid 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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