Transcriptomics

Dataset Information

4

Genome sequencing of childhood medulloblastoma brain tumors links chromothripsis with TP53 mutations


ABSTRACT: Genomic rearrangements typically occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving chromosome shattering and reshuffling ('chromothripsis'), for which no genetic basis has yet been described. Whole-genome sequencing of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome) revealed massive, complex rearrangements resulting from chromothripsis. Integrating TP53 status with genomic rearrangement data in additional medulloblastomas revealed a striking association between TP53 mutation and chromothripsis in SHH-MBs. Unexpectedly, five seemingly sporadic SHH-MB patients with chromothripsis harbored TP53 germline mutations – findings relevant for clinical management. Analysis of additional tumor entities substantiated a link between TP53 mutation and chromothripsis, beyond general genomic instability. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings implicate p53 in the initiation of, or cellular reaction to, chromothripsis – a novel role for the 'guardian of the genome'. The DNA copy-number profiles of 11 primary medulloblastoma samples were analyzed on the Affymetrix Mapping250K Nsp array, together with data from 70 primary samples taken from GSE21140. Data from diploid reference samples were taken from GSE9222. Additionally, DNA copy-number profiles for 19 additional medulloblastoma samples were generated on the Affymetrix SNP6 platform with matched blood samples.

ORGANISM(S): Homo sapiens  

SUBMITTER: Vladimir Benes   Huriye Cin  Dianna Martin  Peter Lichter  Marcel Kool  David T Jones  David Malkin  Cynthia Hawkins  Adam Fontebasso  Tobias Rausch  David Shih  Hendrik Witt  Marc Zapatka  Olaf Witt  Jan J Molenaar  Christian Beck  Joachim Weischenfeldt  David J. H. Shih  Wolfram Scheurlen  Andrey Korshunov  Jonathan Wasserman  Cindy Zhang  Sabrina Pleier  Elke Pfaff  Jelena Tica  Rogier Versteeg  Thomas Zichner  Lars Bullinger  Volkmar Hans  Nada Jabado  Stefan M Pfister  Luca Massimi  Rinnat Porat  Paul A Northcott  Andreas E Kulozik  Diana Merino  Jonathon Blake  Roland Eils  Jan Koster  Andreas von Deimling  Frank Rücker  Sebastian Bender  Natalie Jäger  Michael D Taylor  Hartmut Döhner  Adrian M Stütz  Jan O Korbel  Qi Wang  Marc Remke  Benedikt Brors  Konstanze Döhner  Uri Tabori 

PROVIDER: E-GEOD-34258 | ArrayExpress | 2012-01-20

SECONDARY ACCESSION(S): GSE34258PRJNA149743

REPOSITORIES: GEO, ArrayExpress

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