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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 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.

SUBMITTER: Johnson RA

PROVIDER: S-EPMC2912966 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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

Johnson Robert A RA Wright Karen D KD Poppleton Helen H Mohankumar Kumarasamypet M KM Finkelstein David D Pounds Stanley B SB Rand Vikki V Leary Sarah E S SE White Elsie E Eden Christopher C Hogg Twala T Northcott Paul P Mack Stephen S Neale Geoffrey G Wang Yong-Dong YD Coyle Beth B Atkinson Jennifer J DeWire Mariko M Kranenburg Tanya A TA Gillespie Yancey Y Allen Jeffrey C JC Merchant Thomas T Boop Fredrick A FA Sanford Robert A RA Gajjar Amar A Ellison David W DW Taylor Michael D MD Grundy Richard G RG Gilbertson Richard J RJ

Nature 20100718 7306

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 ...[more]

PMID: 20639864

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Project description:Genomic technologies have unmasked molecularly distinct subgroups among tumors of the same histological type; but understanding the biologic basis of these subgroups has proved difficult since their defining alterations are often numerous, and the cellular origins of most cancers remain unknown. We sought to decipher complex genomic data sets by matching the genetic alterations contained within these, with candidate cells of origin, to generate accurate disease models. Using an integrated genomic analysis we first identified subgroups of human ependymoma: a form of neural tumor that arises throughout the central nervous system (CNS). Validated alterations included amplifications and homozygous deletions of genes not yet implicated in ependymoma. Matching the transcriptomes of human ependymoma subgroups to those of distinct types of mouse radial glia (RG)—neural stem cells (NSCs) that we identified previously to be a candidate cell of origin of ependymoma - allowed us to select RG types most likely to represent cells of origin of disease subgroups. The transcriptome of human cerebral ependymomas that amplify EPHB2 and delete INK4A/ARF matched most closely that of embryonic cerebral Ink4a/Arf-/- RG: remarkably, activation of EphB2 signaling in this RG type, but not others, generated highly penetrant ependymomas that modeled accurately the histology and transcriptome of one human cerebral tumor subgroup (subgroup ‘D’). Further comparative genomic analysis revealed selective alterations in the copy number and expression of genes that regulate neural differentiation, particularly synaptogenesis, in both mouse and human subgroup ‘D’ ependymomas; pinpointing this pathway as a previously unknown target of ependymoma tumorigenesis. Our data demonstrate the power of comparative genomics to sift complex genetic data sets to identify key molecular alterations in cancer subgroups. [human mRNA] samples: 83 human ependynoma primary tumors were collected and clustered into distinct classes by unsupervised methods and then compared to mouse model data. [mouse mRNA] samples: 192 mouse tumors and cell lines were collected and clustered into distinct classes by unsupervised methods and then compared to human tumors. [human miRNA] samples: 64 human ependynoma primary tumors were collected and miRNA expression was assesed and compared to genomic expression

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

Publications

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

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