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| Status |
Public on Jan 20, 2012 |
| Title |
Genome sequencing of childhood medulloblastoma brain tumors links chromothripsis with TP53 mutations |
| Organism |
Homo sapiens |
| Experiment type |
Genome variation profiling by SNP array
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| Summary |
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'.
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| Overall design |
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 GSE14437. 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.
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| Contributor(s) |
Rausch T, Jones DT, Zapatka M, Stütz AM, Zichner T, Weischenfeldt J, Jäger N, Remke M, Shih D, Northcott PA, Pfaff E, Tica J, Wang Q, Massimi L, Witt H, Bender S, Pleier S, Cin H, Hawkins C, Beck C, von Deimling A, Hans V, Brors B, Eils R, Scheurlen W, Blake J, Benes V, Kulozik AE, Witt O, Martin D, Zhang C, Porat R, Merino D, Wasserman J, Jabado N, Fontebasso A, Bullinger L, Rücker F, Döhner K, Döhner H, Koster J, Molenaar JJ, Versteeg R, Kool M, Tabori U, Malkin D, Korshunov A, Taylor MD, Lichter P |
| Citation(s) |
22265402 |
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| Submission date |
Dec 08, 2011 |
| Last update date |
Nov 27, 2018 |
| Contact name |
David J. H. Shih |
| E-mail(s) |
david.shih@utoronto.ca
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| Phone |
(416) 813-7654
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| Organization name |
Hospital for Sick Children
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| Department |
Developmental and Stem Cell Biology
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| Lab |
Peter Gilgan Centre for Research and Learning
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| Street address |
686 Bay St
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| City |
Toronto |
| State/province |
ON |
| ZIP/Postal code |
M5G 0A4 |
| Country |
Canada |
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| Platforms (2) |
| GPL3718 |
[Mapping250K_Nsp] Affymetrix Mapping 250K Nsp SNP Array |
| GPL6801 |
[GenomeWideSNP_6] Affymetrix Genome-Wide Human SNP 6.0 Array |
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| Samples (49)
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| Relations |
| BioProject |
PRJNA149743 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE34258_RAW.tar |
1.4 Gb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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