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Dissecting the genomic complexity underlying medulloblastoma

Lookup NU author(s): Dr Daniel Williamson, Professor Steven Clifford

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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(1). 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(2,3). WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens(4). SHH tumours show hedgehog pathway activation, and have an intermediate prognosis(2). Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges(2,3,5). 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.


Publication metadata

Author(s): Jones DTW, Jager N, Kool M, Zichner T, Hutter B, Sultan M, Cho YJ, Pugh TJ, Hovestadt V, Stutz AM, Rausch T, Warnatz HJ, 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 UD, Wang Q, Lasitschka B, Bartholomae CC, 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 MJ, Russell RB, Coco S, Tonini GP, Schuller U, Hans V, Graf N, Kim YJ, Monoranu C, Roggendorf W, Unterberg A, Herold-Mende C, Milde T, Kulozik AE, von Deimling A, Witt O, Maass E, Rossler J, Ebinger M, Schuhmann MU, Fruhwald MC, Hasselblatt M, Jabado N, Rutkowski S, von Bueren AO, Williamson D, Clifford SC, McCabe MG, Collins VP, Wolf S, Wiemann S, Lehrach H, Brors B, Scheurlen W, Felsberg J, Reifenberger G, Northcott PA, Taylor MD, Meyerson M, Pomeroy SL, Yaspo ML, Korbel JO, Korshunov A, Eils R, Pfister SM, Lichter P

Publication type: Article

Publication status: Published

Journal: Nature

Year: 2012

Volume: 488

Issue: 7409

Pages: 100-105

Print publication date: 25/07/2012

ISSN (print): 0028-0836

ISSN (electronic): 1476-4687

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/nature11284

DOI: 10.1038/nature11284


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Funding

Funder referenceFunder name
Italian Neuroblastoma Foundation
Pediatric Brain Tumor Foundation
Samantha Dickson Brain Tumour Trust
German Cancer Research Center-Heidelberg Center for Personalized Oncology (DKFZ-HIPO)
Max Planck Society
PedBrain Tumor Project contributing to the International Cancer Genome Consortium (ICGC PedBrain Tumor Project)
109252German Cancer Aid
01GS0883German Federal Ministry of Education and Research (BMBF)
BS-2007-04UK Children's Cancer and Leukaemia Group (CCLG)

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