Subgroup-specific structural variation across 1,000 medulloblastoma genomes

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular v...

Full description

Saved in:

Bibliographic Details
Published in:	Nature (London) Vol. 488; no. 7409; pp. 49 - 56
Main Authors:	Peacock, John, Zichner, Thomas, Stütz, Adrian M., Reimand, Jüri, Schumacher, Steven E., Ellison, David W., Marshall, Christian R., Lionel, Anath C., Mack, Stephen, Yao, Yuan, Ramaswamy, Vijay, Luu, Betty, Rolider, Adi, Cavalli, Florence M. G., Wang, Xin, Remke, Marc, Wu, Xiaochong, Chiu, Readman Y. B., Chuah, Eric, Corbett, Richard D., Hoad, Gemma R., Jackman, Shaun D., Lo, Allan, Mungall, Karen L., Qian, Jenny Q., Raymond, Anthony G. J., Varhol, Richard J., Birol, Inanc, Moore, Richard A., Mungall, Andrew J., Holt, Robert, Kawauchi, Daisuke, Roussel, Martine F., Jones, David T. W., Fernandez-L, Africa, Kenney, Anna M., Dirks, Peter, Aviv, Tzvi, Grajkowska, Wieslawa A., Perek-Polnik, Marta, Delattre, Olivier, Reynaud, Stéphanie S., Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Scheurlen, Wolfram, Eberhart, Charles G., Fèvre-Montange, Michelle, Jouvet, Anne, Pollack, Ian F., Fan, Xing, Muraszko, Karin M., Yancey Gillespie, G., Di Rocco, Concezio, Massimi, Luca, French, Pim J., Kros, Johan M., Ellenbogen, Richard G., Kren, Leos, Thompson, Reid C., Fontebasso, Adam, Albrecht, Steffen, Lindsey, Janet C., Bailey, Simon, Weiss, William A., Bognár, László, Klekner, Almos, Van Meter, Timothy E., Kumabe, Toshihiro, Tominaga, Teiji, Elbabaa, Samer K., Leonard, Jeffrey R., Liau, Linda M., Van Meir, Erwin G., Fouladi, Maryam, Garami, Miklós, Hauser, Peter, Saad, Ali G., Iolascon, Achille, Jung, Shin, Carlotti, Carlos G., Robinson, Shenandoah, Zollo, Massimo, Chan, Jennifer A., Levy, Michael L., Sorensen, Poul H. B., Meyerson, Matthew, Pomeroy, Scott L., Cho, Yoon-Jae, Bader, Gary D., Tabori, Uri, Hawkins, Cynthia E., Bouffet, Eric, Scherer, Stephen W., Rutka, James T., Malkin, David, Clifford, Steven C., Korbel, Jan O., Marra, Marco A., Taylor, Michael D.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 02-08-2012 Nature Publishing Group
Subjects:	631/208/68 631/208/726/649/2157 631/67/1922 Biological and medical sciences Brain tumors Cancer Carrier Proteins - genetics Cerebellar Neoplasms - classification Cerebellar Neoplasms - genetics Cerebellar Neoplasms - metabolism Child DNA Copy Number Variations - genetics Gene Duplication - genetics Genes Genes, myc - genetics Genetic aspects Genetic variation Genome, Human - genetics Genomes Genomic Structural Variation - genetics Genomics Hedgehog Proteins - metabolism Heterogeneity Humanities and Social Sciences Humans Medical sciences Medulloblastoma Medulloblastoma - classification Medulloblastoma - genetics Medulloblastoma - metabolism Metastasis multidisciplinary Nerve Tissue Proteins - genetics Neurology NF-kappa B - metabolism Oncogene Proteins, Fusion - genetics Parkinson's disease Physiological aspects Proteins - genetics RNA, Long Noncoding Science Science (multidisciplinary) Signal Transduction Transforming Growth Factor beta - metabolism Translocation, Genetic - genetics Tumors of the nervous system. Phacomatoses United States Nervous system diseases Genetic variability Medulloblastoma Central nervous system disease Malignant tumor Genome Cancer Cerebral disorder
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP , a gene associated with Parkinson’s disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1 , including PVT1-MYC and PVT1-NDRG1 , that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy. Medulloblastoma is the most common malignant brain tumour in children; having assembled over 1,000 samples the authors report that somatic copy number aberrations are common in medulloblastoma, in particular a tandem duplication of SNCAIP , a gene associated with Parkinson’s disease, which is restricted to subgroup 4α, and translocations of PVT1 , which are restricted to Group 3. The medulloblastoma genome dissected Medulloblastoma is the most common malignant brain tumour in children. Four papers published in the 2 August 2012 issue of Nature use whole-genome and other sequencing techniques to produce a detailed picture of the genetics and genomics of this condition. Notable findings include the identification of recurrent mutations in genes not previously implicated in medulloblastoma, with significant genetic differences associated with the four biologically distinct subgroups and clinical outcomes in each. Potential avenues for therapy are suggested by the identification of targetable somatic copy-number alterations, including recurrent events targeting TGFβ signalling in Group 3, and NF-κB signalling in Group 4 medulloblastomas.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally
ISSN:	0028-0836 1476-4687
DOI:	10.1038/nature11327