Dissecting the genomic complexity underlying medulloblastoma

Jones, D. T.; Kool, M.; Jäger, N.; Zichner, T.; Hutter, B.; Sultan, Marc; Cho, Y. J.; Pugh, T. J.; Hovestadt, V.; Stütz, A. M.; Rausch, T.; Warnatz, Hans Jörg; Ryzhova, M.; Bender, S.; Sturm, D.; Pleier, S.; Cin, H.; Pfaff, E.; Sieber, L.; Wittmann, A.; Remke, M.; Witt, H.; Hutter, S.; Tzaridis, T.; Weischenfeldt, J.; Raeder, B.; Avci, M.; Amstislavskiy, V.; Zapatka, M.; Weber, U. D.; Wang, Q.; Lasitschka, B.; Bartholomae, C. C.; Schmidt, M.; von Kalle, C.; Ast, V.; Lawerenz, C.; Eils, J.; Kabbe, R.; Benes, V.; van Sluis, P.; Koster, J.; Volckmann, R.; Shih, D.; Betts, M. J.; Russell, R. B.; Coco, S.; Tonini, G. P.; Schuller, U.; Hans, V.; Graf, N.; Kim, Y. J.; Monoranu, C.; Roggendorf, W.; Unterberg, A.; Herold-Mende, C.; Milde, T.; Kulozik, A. E.; von Deimling, A.; Witt, O.; Maass, E.; Rossler, J.; Ebinger, M.; Schuhmann, M. U.; Fruhwald, M. C.; Hasselblatt, M.; Jabado, N.; Rutkowski, S.; von Bueren,; Williamson, D.; Clifford, S. C.; McCabe, M. G.; Collins, V. P.; Wolf, S.; Wiemann, S.; Lehrach, H.; Brors, B.; Scheurlen, W.; Felsberg, J.; Reifenberger, G.; Northcott, P. A.; Taylor, M. D.; Meyerson, M.; Pomeroy, S. L.; Yaspo, M. L.; Korbel, J. O.; Korshunov, A.; Eils, R.; Pfister, S. M.; Lichter, P.

doi:10.1038/nature11284

Dissecting the genomic complexity underlying medulloblastoma

Jones, D. T., Kool, M., Jäger, N., Zichner, T., Hutter, B., Sultan, M., Cho, Y. J., Pugh, T. J., Hovestadt, V., Stütz, A. M., Rausch, T., Warnatz, H. J., Ryzhova, M., Bender, S., Sturm, D., Pleier, S., Cin, H., Pfaff, E., Sieber, L., Wittmann, A., Remke, M., Witt, H., Hutter, S., Tzaridis, T., Weischenfeldt, J., Raeder, B., Avci, M., Amstislavskiy, V., Zapatka, M., Weber, U. D., Wang, Q., Lasitschka, B., Bartholomae, C. C., Schmidt, M., von Kalle, C., Ast, V., Lawerenz, C., Eils, J., Kabbe, R., Benes, V., van Sluis, P., Koster, J., Volckmann, R., Shih, D., Betts, M. J., Russell, R. B., Coco, S., Tonini, G. P., Schuller, U., Hans, V., Graf, N., Kim, Y. J., Monoranu, C., Roggendorf, W., Unterberg, A., Herold-Mende, C., Milde, T., Kulozik, A. E., von Deimling, A., Witt, O., Maass, E., Rossler, J., Ebinger, M., Schuhmann, M. U., Fruhwald, M. C., Hasselblatt, M., Jabado, N., Rutkowski, S., von Bueren, Williamson, D., Clifford, S. C., McCabe, M. G., Collins, V. P., Wolf, S., Wiemann, S., Lehrach, H., Brors, B., Scheurlen, W., Felsberg, J., Reifenberger, G., Northcott, P. A., Taylor, M. D., Meyerson, M., Pomeroy, S. L., Yaspo, M. L., Korbel, J. O., Korshunov, A., Eils, R., Pfister, S. M., & Lichter, P. (2012). Dissecting the genomic complexity underlying medulloblastoma. Nature, 488(7409), 100-105. doi:10.1038/nature11284.

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アイテムのパーマリンク: https://hdl.handle.net/11858/00-001M-0000-000E-F051-6 版のパーマリンク: https://hdl.handle.net/11858/00-001M-0000-000E-F052-4

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2012

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作成者:
Jones, D. T., 著者
Kool, M., 著者
Jäger, N., 著者
Zichner, T., 著者
Hutter, B., 著者
Sultan, Marc¹, 著者
Cho, Y. J., 著者
Pugh, T. J., 著者
Hovestadt, V., 著者
Stütz, A. M., 著者
Rausch, T., 著者
Warnatz, Hans Jörg¹, 著者
Ryzhova, M., 著者
Bender, S., 著者
Sturm, D., 著者
Pleier, S., 著者
Cin, H., 著者
Pfaff, E., 著者
Sieber, L., 著者
Wittmann, A., 著者
Remke, M., 著者Witt, H., 著者Hutter, S., 著者Tzaridis, T., 著者Weischenfeldt, J., 著者Raeder, B., 著者Avci, M., 著者Amstislavskiy, V., 著者Zapatka, M., 著者Weber, U. D., 著者Wang, Q., 著者Lasitschka, B., 著者Bartholomae, C. C., 著者Schmidt, M., 著者von Kalle, C., 著者Ast, V., 著者Lawerenz, C., 著者Eils, J., 著者Kabbe, R., 著者Benes, V., 著者van Sluis, P., 著者Koster, J., 著者Volckmann, R., 著者Shih, D., 著者Betts, M. J., 著者Russell, R. B., 著者Coco, S., 著者Tonini, G. P., 著者Schuller, U., 著者Hans, V., 著者Graf, N., 著者Kim, Y. J., 著者Monoranu, C., 著者Roggendorf, W., 著者Unterberg, A., 著者Herold-Mende, C., 著者Milde, T., 著者Kulozik, A. E., 著者von Deimling, A., 著者Witt, O., 著者Maass, E., 著者Rossler, J., 著者Ebinger, M., 著者Schuhmann, M. U., 著者Fruhwald, M. C., 著者Hasselblatt, M., 著者Jabado, N., 著者Rutkowski, S., 著者von Bueren, 著者Williamson, D., 著者Clifford, S. C., 著者McCabe, M. G., 著者Collins, V. P., 著者Wolf, S., 著者Wiemann, S., 著者Lehrach, H., 著者Brors, B., 著者Scheurlen, W., 著者Felsberg, J., 著者Reifenberger, G., 著者Northcott, P. A., 著者Taylor, M. D., 著者Meyerson, M., 著者Pomeroy, S. L., 著者Yaspo, M. L., 著者Korbel, J. O., 著者Korshunov, A., 著者Eils, R., 著者Pfister, S. M., 著者Lichter, P., 著者全て表示

所属:
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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キーワード: 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

要旨: 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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言語: eng - English

日付: 投稿: 2012-02-03受理: 2012-06-06オンライン出版: 2012-07-25出版: 2012

出版の状態: 出版

ページ: 5

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識別子（DOI, ISBNなど）: DOI: 10.1038/nature11284

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出版物名: Nature

種別: 学術雑誌

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ページ: - 巻号: 488 (7409) 通巻号: - 開始・終了ページ: 100 - 105 識別子（ISBN, ISSN, DOIなど）: ISSN: 1749-4885
CoNE: https://pure.mpg.de/cone/journals/resource/1000000000240270

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