In vivo oncogenomics screen identifies novel ependymoma oncogenes and tumor suppressor genes within large chromosomal alterations
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE67497 | GEO | 2015/04/28
SECONDARY ACCESSION(S): PRJNA280083
REPOSITORIES: GEO
Similar Datasets
Project description:Cancers are characterized by non-random, chromosome copy number variations that presumably contain oncogenes and tumor suppressor genes (TSGs). The affected loci are often large, making it difficult to pinpoint which genes are driving the cancer. Here, we report a cross-species, in vivo screen of 84 candidate oncogenes and 39 candidate TSGs, located within 28 recurrent chromosomal alterations in ependymoma. Through a series of mouse models we validate eight new ependymoma oncogenes and 11 TSGs that dysregulate a small number of cell functions including vesicle trafficking and cholesterol biosynthesis; pinpointing these as potential points for therapeutic intervention. Mouse cortical tumors were excised. These tumors derived from cells expressing one of 3 genes: RAB3A, BC74C, or ZNF668
2015-04-28 | E-GEOD-67497 | biostudies-arrayexpress
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
2010-07-19 | E-GEOD-21687 | biostudies-arrayexpress
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.
2010-07-19 | GSE21687 | GEO
Project description:Genome sequencing studies have uncovered the most frequent mutations in cancer and novel targets for therapy. While successful in many tumors, this approach has failed in others. Lethal infant ependymomas (Group A) lies at the far end of this spectrum with no recurrent focal genomic alterations, no recurrent somatic mutations, and no clear driver for targeted therapy. Despite a paucity of genetic aberrations, Group A ependymomas demonstrate widespread epigenetic alterations. We therefore sought to interrogate the oncogenic drivers of ependymoma by characterizing the enhancer landscapes of 30 primary tumors. Super enhancer (SE) mapping revealed novel ependymoma oncogenes such as PAX6, SKI, and FGFRL1 and uncovered subgroup specific SE lesions across ependymoma, specifically, in Group A such as PAX3, MEIS1, and IGF2BP1. Finally, we identified SE associated gene dependencies that maintain FGFR1 and WEE1 expression in ependymoma, demonstrating the utility of SE lesions to predict novel targets for cancer therapy.
2018-11-15 | GSE75017 | GEO
Project description:We compared molecular characteristics of primary and recurrent pediatric ependymoma to identify sub-group specific differences. Gene expression profiles were used to identify unique immunobiologic sub-types of posterior fossa pediatric ependymoma. Gene expression profiles were generated from surgical tumor (ependymoma) (n=65) using Affymetrix HG-U133plus2 chips (Platform GPL570). Normalization was performed on our entire cohort of ependymoma. Of the 65 samples, a sub-set of 58 were used in the corresponding manuscript. Excluded samples are noted. Gene expression profiles were filtered to obtain gene expression of key immune cell markers. Comparative analyses between tumor samples were used to identifiy unique immunobiology between posterior fossa sub-groups.
2013-08-30 | E-GEOD-50385 | biostudies-arrayexpress
Project description:Pediatric ependymoma has relatively low frequencies of DNA mutations, which suggest that epigenetics may drive tumors. However, the epigenetic mechanisms for recurrent ependymoma are still poorly understood. Here, we performed longitudinal and comprehensive DNA methylation and gene expression analysis for recurrent pediatric ependymoma tumors from 10 patients, total 46 DNA methylomes (including primary tumors and matched recurrent tumors; normal pediatric brain tissues and PDOX tumors). Both RELA and PFA tumors maintained the subtype DNA methylation signatures during repeated relapses. We further identified the potential DNA methylation predictors, drivers and boosters and their potential regulated genes for recurrent ependymoma tumors. Increased DNA methylation levels within H3K4me1 enriched regions indicates disturbed functions of LSD1 gene in recurrent ependymoma tumors. Combining novel LSD1 inhibitor SYC-836 with radiation (XRT) significantly prolonged animal survival times in PDOX models of recurrent PFA ependymoma. Our PDOX models provide a unique platform for preclinical testing drugs and development of new therapy for pediatric recurrent ependymoma.
2022-07-12 | GSE156619 | GEO
Project description:We compared molecular characteristics of primary and recurrent pediatric ependymoma to identify sub-group specific differences. Gene expression profiles were used to identify unique immunobiologic sub-types of posterior fossa pediatric ependymoma.
2013-08-30 | GSE50385 | GEO
Project description:YAP1 gene fusions have been observed in a subset of paediatric ependymomas. Here we show that, ectopic expression of active nuclear YAP1 (nlsYAP5SA) in ventricular zone neural progenitor cells using conditionally-induced NEX/NeuroD6-Cre is sufficient to drive brain tumour formation in mice. Neuronal differentiation is inhibited in the hippocampus. Deletion of YAP1’s negative regulators LATS1 and LATS2 kinases in NEX-Cre lineage in double conditional knockout mice also generates similar tumours, which are rescued by deletion of YAP1 and its paralog TAZ. YAP1/TAZ-induced mouse tumours display molecular and ultrastructural characteristics of human ependymoma. RNA sequencing and quantitative proteomics of mouse tumours demonstrate similarities to YAP1-fusion induced supratentorial ependymoma. Finally, we find that transcriptional cofactor HOPX is upregulated in mouse models and in human YAP1-fusion induced ependymoma, supporting their similarity. Our results show that uncontrolled YAP1/TAZ activity in neuronal precursor cells leads to ependymoma-like tumours in mice.
2020-05-26 | PXD018131 | Pride
Project description:Despite histological similarity of ependymomas from throughout the neuraxis, the disease likely comprises multiple independent entities, each with a distinct molecular pathogenesis. Transcriptional profiling of two large independent cohorts of ependymomas reveals the existence of two demographically, transcriptionally, genetically and clinically distinct groups of posterior fossa (PF) ependymoma. Group A patients are younger, have laterally located tumors with a balanced genome, and are much more likely to exhibit recurrence, metastasis, and death as compared to Group B patients. Identification and optimization of immunohistochemical markers for PF ependymoma subgroups allowed validation of our findings on a third group of independent ependymomas using a human ependymoma tissue microarray, and provides a tool for prospective prognostication and stratification of PF ependymoma patients. This SuperSeries is composed of the following subset Series: GSE27283: Human ependymoma samples [expression] GSE27286: Human ependymoma samples, Subgrouping [aCGH - German Cancer Research Center human 33K BAC array] Refer to individual Series
2011-08-14 | E-GEOD-27287 | biostudies-arrayexpress
Project description:Whole-genome transcriptional profiling of human ependymoma tumors. Subgrouping based on mRNA expression profile. Fresh frozen tumor material was collected during tumor resection. Gene expression profiles illustrate distinct expression pattern at diagnosis.
2011-08-14 | E-GEOD-27283 | biostudies-arrayexpress