Genome Sequencing of Pediatric Medulloblastoma Links Catastrophic DNA Rearrangements with TP53 Mutations

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• 作者：Tobias Rausch¹ ; ¹⁸ ; David  ; T.W. Jones² ; ¹⁸ ; Marc Zapatka² ; ¹⁸ ; Adrian  ; M. Stü ; tz¹ ; ¹⁸ ; Thomas Zichner¹ ; Joachim Weischenfeldt¹ ; Natalie Jä ; ger³ ; Marc Remke² ; ⁵ ; David Shih⁶ ; Paul  ; A. Northcott⁶ ; Elke Pfaff² ; Jelena Tica¹ ; Qi Wang⁵ ; Luca Massimi⁷ ; Hendrik Witt² ; ⁵ ; Sebastian Bender² ; ⁵ ; Sabrina Pleier² ; ⁵ ; Huriye Cin² ; Cynthia Hawkins⁶ ; ⁸ ; Christian Beck⁵ ; Andreas von  ; Deimling⁹ ; Volkmar Hans¹⁰ ; Benedikt Brors³ ; Roland Eils³ ; ²⁰ ; Wolfram Scheurlen¹¹ ; Jonathon Blake¹ ; Vladimir Benes¹ ; Andreas  ; E. Kulozik⁵ ; Olaf Witt⁵ ; ⁴ ; Dianna Martin¹² ; Cindy Zhang¹² ; Rinnat Porat¹² ; Diana M. Merino¹² ; Jonathan Wasserman¹² ; Nada Jabado¹³ ; Adam Fontebasso¹³ ; Lars Bullinger¹⁴ ; Frank G. Rü ; cker¹⁴ ; Konstanze Dö ; hner¹⁴ ; Hartmut Dö ; hner¹⁴ ; Jan Koster¹⁵ ; Jan  ; J. Molenaar¹⁵ ; Rogier Versteeg¹⁵ ; Marcel Kool² ; Uri Tabori⁶ ; ¹² ; David Malkin¹² ; Andrey Korshunov⁹ ; Michael  ; D. Taylor⁶ ; ¹⁶ ; Peter Lichter² ; ¹⁹ ; ^{peter.lichter@dkfz-heidelberg.de} ; Stefan  ; M. Pfister² ; ⁵ ; ¹⁹ ; ^{s.pfister@dkfz-heidelberg.de} ; Jan  ; O. Korbel¹ ; ¹⁷ ; ¹⁹ ; ^{jan.korbel@embl-heidelberg.de}
• 刊名：Cell
• 出版年：2012
• 出版时间：20 January 2012
• 年：2012
• 卷：148
• 期：1-2
• 页码：59-71
• 全文大小：1765 K

文摘

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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.