Publication Date:
2010-07-20
Description:
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 unknown. 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2912966/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2912966/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Johnson, Robert A -- Wright, Karen D -- Poppleton, Helen -- Mohankumar, Kumarasamypet M -- Finkelstein, David -- Pounds, Stanley B -- Rand, Vikki -- Leary, Sarah E S -- White, Elsie -- Eden, Christopher -- Hogg, Twala -- Northcott, Paul -- Mack, Stephen -- Neale, Geoffrey -- Wang, Yong-Dong -- Coyle, Beth -- Atkinson, Jennifer -- DeWire, Mariko -- Kranenburg, Tanya A -- Gillespie, Yancey -- Allen, Jeffrey C -- Merchant, Thomas -- Boop, Fredrick A -- Sanford, Robert A -- Gajjar, Amar -- Ellison, David W -- Taylor, Michael D -- Grundy, Richard G -- Gilbertson, Richard J -- P01 CA096832/CA/NCI NIH HHS/ -- P01 CA096832-06A18120/CA/NCI NIH HHS/ -- P01 CA096832-078120/CA/NCI NIH HHS/ -- P01CA96832/CA/NCI NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- P30 CA021765-319030/CA/NCI NIH HHS/ -- P30CA021765/CA/NCI NIH HHS/ -- R01 CA129541/CA/NCI NIH HHS/ -- R01 CA129541-01/CA/NCI NIH HHS/ -- R01 CA129541-02/CA/NCI NIH HHS/ -- R01 CA129541-03/CA/NCI NIH HHS/ -- R01 CA129541-04/CA/NCI NIH HHS/ -- R01CA129541/CA/NCI NIH HHS/ -- T32 CA070089/CA/NCI NIH HHS/ -- England -- Nature. 2010 Jul 29;466(7306):632-6. doi: 10.1038/nature09173. Epub 2010 Jul 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Developmental Neurobiology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20639864" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
*Cell Compartmentation
;
Central Nervous System/cytology/growth & development
;
Central Nervous System Neoplasms/classification/genetics/pathology
;
*Disease Models, Animal
;
Ependymoma/classification/*genetics/*pathology
;
Gene Deletion
;
Gene Expression Profiling
;
Gene Expression Regulation, Neoplastic
;
Genes, p16
;
*Genomics
;
Humans
;
Mice
;
Models, Biological
;
Mutation/*genetics
;
Polymorphism, Single Nucleotide/genetics
;
Receptor, EphB2/genetics/metabolism
;
Species Specificity
;
Stem Cells/cytology/metabolism
;
Synapses/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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