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Subgroup-specific structural variation across 1,000 medulloblastoma genomes

Lookup NU author(s): Dr Janet Lindsey, Professor Simon Bailey, Professor Steven Clifford

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Abstract

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 4 alpha. 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-beta signalling in Group 3, and NF-kappa B signalling in Group 4, suggest future avenues for rational, targeted therapy.


Publication metadata

Author(s): Northcott PA, Shih DJH, Peacock J, Garzia L, Morrissy AS, Zichner T, Stutz AM, Korshunov A, Reimand J, Schumacher SE, Beroukhim R, Ellison DW, Marshall CR, Lionel AC, Mack S, Dubuc A, Yao Y, Ramaswamy V, Luu B, Rolider A, Cavalli FMG, Wang X, Remke M, Wu XC, Chiu RYB, Chu A, Chuah E, Corbett RD, Hoad GR, Jackman SD, Li YS, Lo A, Mungall KL, Nip KM, Qian JQ, Raymond AGJ, Thiessen N, Varhol RJ, Birol I, Moore RA, Mungall AJ, Holt R, Kawauchi D, Roussel MF, Kool M, Jones DTW, Witt H, Fernandez-L A, Kenney AM, Wechsler-Reya RJ, Dirks P, Aviv T, Grajkowska WA, Perek-Polnik M, Haberler CC, Delattre O, Reynaud SS, Doz FF, Pernet-Fattet SS, Cho BK, Kim SK, Wang KC, Scheurlen W, Eberhart CG, Fevre-Montange M, Jouvet A, Pollack IF, Fan X, Muraszko KM, Gillespie GY, Di Rocco C, Massimi L, Michiels EMC, Kloosterhof NK, French PJ, Kros JM, Olson JM, Ellenbogen RG, Zitterbart K, Kren L, Thompson RC, Cooper MK, Lach B, McLendon RE, Bigner DD, Fontebasso A, Albrecht S, Jabado N, Lindsey JC, Bailey S, Gupta N, Weiss WA, Bognar L, Klekner A, Van Meter TE, Kumabe T, Tominaga T, Elbabaa SK, Leonard JR, Rubin JB, Liau LM, Van Meir EG, Fouladi M, Nakamura H, Cinalli G, Garami M, Hauser P, Saad AG, Iolascon A, Jung S, Carlotti CG, Vibhakar R, Ra YS, Robinson S, Zollo M, Faria CC, Chan JA, Levy ML, Sorensen PHB, Meyerson M, Pomeroy SL, Cho YJ, Bader GD, Tabori U, Hawkins CE, Bouffet E, Scherer SW, Rutka JT, Malkin D, Clifford SC, Jones SJM, Korbel JO, Pfister SM, Marra MA, Taylor MD

Publication type: Article

Publication status: Published

Journal: Nature

Year: 2012

Volume: 488

Issue: 7409

Pages: 49-56

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/nature11327

DOI: 10.1038/nature11327


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Funding

Funder referenceFunder name
B.R.A.I.N. Child
BC Cancer Foundation
Brain Tumour Foundation for Children
Chief of Research Fund
Children's Discovery Institute
CIHR Clinician-Scientist Phase II award
Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre
Montreal Children's Hospital Foundation
Restracomp Fellowship (Hospital for Sick Children)
Southeastern Brain Tumour Foundation
The Family of Kathleen Lorette
University of Toronto McLaughlin Centre
Cancer Genetics Program
Clark H. Smith Brain Tumour Centre
Garron Family Cancer Centre
Government of Ontario
Ontario Institute for Cancer Research
Pediatric Brain Tumour Foundation
Sontag Foundation
109252German Cancer Aid
29XS193NCI
28XS100NCI
CA116804NIH
CA86335NIH
AT1-112286CIHR Institute of Cancer Research
ATE-110814CIHR
BS-2007-04UK Children's Cancer and Leukaemia Group (CCLG)
CA138292NIH
CA159859National Institutes of Health

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