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

Abstract

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.

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Figure 1: The ependymoma genome.
Figure 2: Regionally, developmentally and genetically discrete NSCs match subgroups of human ependymoma.
Figure 3: EPHB2 is an ependymoma oncogene that selectively transforms embryonic cerebral Ink4a/Arf −/− NSCs.
Figure 4: Ephb2- driven mouse ependymomas model human subgroup ‘D’ tumours.

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Gene Expression Omnibus

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The microarray data generated during this study has been deposited in GEO under the accession number GSE21687.

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Acknowledgements

R.J.G. holds the Howard C. Schott Research Chair from the Malia’s Cord Foundation, and is supported by grants from the National Institutes of Health (R01CA129541, P01CA96832 and P30CA021765), the Collaborative Ependymoma Research Network (CERN) and by the American Lebanese Syrian Associated Charities (ALSAC). K.D.W. is supported by NRSA Training Grant T32 CA070089. We are grateful to N. Heintz for providing the Blbp–eGFP mouse, T. Pawson for providing mouse Ephb2 cDNA, M. Roussel for the pCX4-IRES-RFP virus, J. Downing and M. Relling for access to 500K SNP profiles of normal human DNA, and the staff of the Hartwell center for Bioinformatics and Biotechnology, Vector Production Core, ARC, AIC and Cell and Tissue Imaging at St Jude Children’s Research Hospital for technical assistance.

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Contributions

R.J.G., R.G.G. and M.D.T. conceived the research and planned experiments. R.A.J. and K.D.W. also planned and conducted the great majority of the experiments under the direction of R.J.G.; A.G., Y.G., J.C.A., M.D.T. and R.G.G. provided human tumour material. All authors contributed experimental expertise and participated in the writing of the manuscript. D.F., S.B.P., Y.-D.W. and G.N. provided bioinformatic expertise. D.W.E. provided pathology review and iFISH analysis.

Corresponding author

Correspondence to Richard J. Gilbertson.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Methods, References, Supplementary Figures 1-6 with legends, Supplementary Table legends 1-6 (see pages 32-33) and Supplementary Tables 1-6. (PDF 9737 kb)

Supplementary Information

This file contains gene cards, which contain a comprehensive summary of the DNA alteration and gene expression within each validated focal amplification and deletion identified in Figure 1 of the main paper. (PDF 24320 kb)

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Johnson, R., Wright, K., Poppleton, H. et al. Cross-species genomics matches driver mutations and cell compartments to model ependymoma. Nature 466, 632–636 (2010). https://doi.org/10.1038/nature09173

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