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Cross-species genomics matches driver mutations and cell compartments to model ependymoma

Lookup NU author(s): Dr Vikki Rand, Professor David Ellison, Dr Richard Gilbertson


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Understanding the biology that underlies histologically similar but molecularly distinct subgroups of cancer has proven difficult because their defining genetic alterations are often numerous, and the cellular origins of most cancers remain unknown1, 2, 3. We sought to decipher this heterogeneity by integrating matched genetic alterations and candidate cells of origin to generate accurate disease models. First, we identified subgroups of human ependymoma, a form of neural tumour that arises throughout the central nervous system (CNS). Subgroup-specific alterations included amplifications and homozygous deletions of genes not yet implicated in ependymoma. To select cellular compartments most likely to give rise to subgroups of ependymoma, we matched the transcriptomes of human tumours to those of mouse neural stem cells (NSCs), isolated from different regions of the CNS at different developmental stages, with an intact or deleted Ink4a/Arf locus (that encodes Cdkn2a and b). The transcriptome of human supratentorial ependymomas with amplified EPHB2 and deleted INK4A/ARF matched only that of embryonic cerebral Ink4a/Arf−/− NSCs. Notably, activation of Ephb2 signalling in these, but not other, NSCs generated the first mouse model of ependymoma, which is highly penetrant and accurately models the histology and transcriptome of one subgroup of human supratentorial tumour. Further, comparative analysis of matched mouse and human tumours revealed selective deregulation in the expression and copy number of genes that control synaptogenesis, pinpointing disruption of this pathway as a critical event in the production of this ependymoma subgroup. Our data demonstrate the power of cross-species genomics to meticulously match subgroup-specific driver mutations with cellular compartments to model and interrogate cancer subgroups.

Publication metadata

Author(s): Johnson RA, Wright KD, Poppleton H, Mohankumar KM, Finkelstein D, Pounds SB, Rand V, Leary SE, White E, Eden C, Hogg T, Northcott P, Mack S, Neale G, Wang YD, Coyle B, Atkinson J, Dewire M, Kranenburg TA, Gillespie Y, Allen JC, Merchant T, Boop FA, Sanford RA, Gajjar A, Ellison DW, Taylor MD, Grundy RG, Gilbertson RJ

Publication type: Article

Publication status: Published

Journal: Nature

Year: 2010

Volume: 466

Issue: 7306

Pages: 632-636

Print publication date: 18/07/2010

ISSN (print): 0028-0836

ISSN (electronic): 1476-4687

Publisher: Nature Publishing Group


DOI: 10.1038/nature09173


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Funder referenceFunder name
American Lebanese Syrian Associated Charities (ALSAC)
Collaborative Ependymoma Research Network (CERN)
P01CA96832National Institutes of Health
R01CA129541National Institutes of Health
P30CA021765National Institutes of Health
T32 CA070089NRSA