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  Dissecting the genomic complexity underlying medulloblastoma

Jones, D. T., Kool, M., Jäger, N., Zichner, T., Hutter, B., Sultan, M., et al. (2012). Dissecting the genomic complexity underlying medulloblastoma. Nature, 488(7409), 100-105. doi:10.1038/nature11284.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-F051-6 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-F052-4
Genre: Journal Article

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Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

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Jones, D. T., Author
Kool, M., Author
Jäger, N., Author
Zichner, T., Author
Hutter, B., Author
Sultan, Marc1, Author              
Cho, Y. J., Author
Pugh, T. J., Author
Hovestadt, V., Author
Stütz, A. M., Author
Rausch, T., Author
Warnatz, Hans Jörg1, Author              
Ryzhova, M., Author
Bender, S., Author
Sturm, D., Author
Pleier, S., Author
Cin, H., Author
Pfaff, E., Author
Sieber, L., Author
Wittmann, A., Author
Remke, M., AuthorWitt, H., AuthorHutter, S., AuthorTzaridis, T., AuthorWeischenfeldt, J., AuthorRaeder, B., AuthorAvci, M., AuthorAmstislavskiy, V., AuthorZapatka, M., AuthorWeber, U. D., AuthorWang, Q., AuthorLasitschka, B., AuthorBartholomae, C. C., AuthorSchmidt, M., Authorvon Kalle, C., AuthorAst, V., AuthorLawerenz, C., AuthorEils, J., AuthorKabbe, R., AuthorBenes, V., Authorvan Sluis, P., AuthorKoster, J., AuthorVolckmann, R., AuthorShih, D., AuthorBetts, M. J., AuthorRussell, R. B., AuthorCoco, S., AuthorTonini, G. P., AuthorSchuller, U., AuthorHans, V., AuthorGraf, N., AuthorKim, Y. J., AuthorMonoranu, C., AuthorRoggendorf, W., AuthorUnterberg, A., AuthorHerold-Mende, C., AuthorMilde, T., AuthorKulozik, A. E., Authorvon Deimling, A., AuthorWitt, O., AuthorMaass, E., AuthorRossler, J., AuthorEbinger, M., AuthorSchuhmann, M. U., AuthorFruhwald, M. C., AuthorHasselblatt, M., AuthorJabado, N., AuthorRutkowski, S., Authorvon Bueren, AuthorWilliamson, D., AuthorClifford, S. C., AuthorMcCabe, M. G., AuthorCollins, V. P., AuthorWolf, S., AuthorWiemann, S., AuthorLehrach, H., AuthorBrors, B., AuthorScheurlen, W., AuthorFelsberg, J., AuthorReifenberger, G., AuthorNorthcott, P. A., AuthorTaylor, M. D., AuthorMeyerson, M., AuthorPomeroy, S. L., AuthorYaspo, M. L., AuthorKorbel, J. O., AuthorKorshunov, A., AuthorEils, R., AuthorPfister, S. M., AuthorLichter, P., Author more..
Affiliations:
1Human Chromosome 21 (Marie-Laure Yaspo), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, Ihnestr. 63-74, Berlin, Germany, ou_1479652              

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Free keywords: Aging/genetics Amino Acid Sequence Cell Transformation, Neoplastic Cerebellar Neoplasms/classification/diagnosis/*genetics/pathology Child Chromatin/metabolism Chromosomes, Human/genetics DEAD-box RNA Helicases/genetics DNA Helicases/genetics DNA-Binding Proteins/genetics Genome, Human/*genetics Genomics Hedgehog Proteins/metabolism High-Throughput Nucleotide Sequencing Histone Demethylases/genetics Humans Medulloblastoma/classification/diagnosis/*genetics/pathology Methylation Mutation/genetics Mutation Rate Neoplasm Proteins/genetics Nuclear Proteins/genetics Oncogene Proteins, Fusion/genetics Phosphoprotein Phosphatases/genetics Polyploidy Receptors, Cell Surface/genetics Sequence Analysis, RNA Signal Transduction T-Box Domain Proteins/genetics Transcription Factors/genetics Wnt Proteins/metabolism beta Catenin/genetics
 Abstract: Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients.

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Language(s): eng - English
 Dates: 2012-02-032012-06-062012-07-252012
 Publication Status: Published in print
 Pages: 5
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1038/nature11284
 Degree: -

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Title: Nature
Source Genre: Journal
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Pages: - Volume / Issue: 488 (7409) Sequence Number: - Start / End Page: 100 - 105 Identifier: ISSN: 1749-4885
CoNE: https://pure.mpg.de/cone/journals/resource/1000000000240270