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GSE26576
Homo sapiens
36 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Purpose: More than 90% of children with diffuse intrinsic pontine glioma (DIPG) die within 2 years of diagnosis. There is a dire need to identify therapeutic targets, however lack of patient material for research has limited progress. We evaluated a large cohort of diffuse intrinsic pontine gliomas (DIPGs) to identify recurrent genomic abnormalities and gene expression signatures underlying DIPG.
Publication Title
Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma.
Sample Metadata Fields
Age, Specimen part, Disease
View Samples- Homo sapiens
- 53 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Purpose: To define copy number alterations and gene expression signatures underlying pediatric high-grade glioma (HGG). Patients and Methods: We conducted a high-resolution analysis of genomic imbalances in 78 de novo pediatric HGG, including 7 diffuse intrinsic pontine gliomas, and 10 HGG cases arising in children who received cranial irradiation for a previous cancer, using Affymetrix 500K GeneChips. Gene expression signatures for 53 tumors were analyzed with Affymetrix U133v2 arrays. Results were compared with publicly available data from adult tumors. Results: Pediatric and adult glioblastoma were clearly distinguished by frequent gain of chromosome 1q (30% vs 9%) and lower frequency of chromosome 7 gain (13% vs 74%), respectively. The most common focal amplifications also differed, with PDGFRA and EGFR predominant in childhood and adult populations respectively. These common alterations in pediatric HGG were detected at higher frequency in irradiation-induced tumors, suggesting that these are initiating events in childhood gliomagenesis. CDKN2A was the most common tumor suppressor gene targeted by homozygous deletion in pediatric HGG. No IDH1 hotspot mutations were found in pediatric tumors, highlighting molecular differences in pathogenesis between childhood HGG and adult secondary glioblastoma. Integrated copy number and gene expression data indicated that deregulated PDGFRA signaling plays a major role in pediatric HGG. Conclusions: Integrated molecular profiling showed substantial differences in the molecular features underlying pediatric and adult HGG, indicating that findings in adult tumors cannot be simply extrapolated to younger patients. PDGFRA may be a useful target for pediatric HGG including diffuse pontine gliomas.
Publication Title
Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease.
Sample Metadata Fields
Age, Disease
View Samples- Homo sapiens
- 10 Downloadable Samples
- Illumina HumanWG-6 v3.0 expression beadchip
Description
Primitive neuro-ectodermal tumours (PNET) of the supratentorial region are rare, highly malignant embryonal brain tumours affecting young children. We recently highlighted the importance of a microRNA cluster housing miR-520g. We utilized the Illumina HumanWG-6 v3 R2 and HumanHT-12 v3 R2 Expression BeadChip platforms to profile the effects of miR-520g on gene expression.
Publication Title
Frequent amplification of a chr19q13.41 microRNA polycistron in aggressive primitive neuroectodermal brain tumors.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus, Homo sapiens
- 275 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
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.
Publication Title
Cross-species genomics matches driver mutations and cell compartments to model ependymoma.
Sample Metadata Fields
Sex, Age, Specimen part, Disease, Disease stage
View Samples- Mus musculus
- 16 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Medulloblastoma encompasses a collection of clinically and molecularly diverse tumor subtypes that together comprise the most common malignant childhood brain tumor. These tumors are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) following aberrant activation of the Sonic Hedgehog pathway (hereafter, SHH-subtype). The pathological processes that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development of much needed new therapies. Here, we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT-subtype), arises outside the cerebellum from cells of the dorsal brainstem. We found that genes marking human WNT-subtype medulloblastomas are more frequently expressed in the lower rhombic lip (LRL) and embryonic dorsal brainstem than in the upper rhombic lip (URL) and developing cerebellum. Magnetic resonance imaging (MRI) and intra-operative reports showed that human WNT-subtype tumors infiltrate the dorsal brainstem, while SHH-subtype tumors are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little impact on progenitor cell populations in the cerebellum, but caused the abnormal accumulation of cells on the embryonic dorsal brainstem that included aberrantly proliferating Zic1+ precursor cells. These lesions persisted in all mutant adult mice and in 15% of cases in which Tp53 was concurrently deleted, progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. We provide the first evidence that subtypes of medulloblastoma have distinct cellular origins. Our data provide an explanation for the marked molecular and clinical differences between SHH and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer.
Publication Title
Subtypes of medulloblastoma have distinct developmental origins.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 37 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
We have discovered two major molecular subgroups of PFA molecular group posterior fossa ependymomas by DNA methylation profiling. These are also distinguished by gene expression profiling using Affymetrix U133v2 arrays with correspondence to data generated by DNA methylation profiling.
Publication Title
Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 71 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. To identify mutations that drive medulloblastoma we sequenced the entire genomes of 37 tumours and matched normal blood. One hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma: several target distinct components of the epigenetic machinery in different disease subgroups, e.g., regulators of H3K27 and H3K4 trimethylation in subgroup-3 and 4 (e.g., KDM6A and ZMYM3), and CTNNB1-associated chromatin remodellers in WNT-subgroup tumours (e.g., SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours, identified genes that maintain this cell lineage (DDX3X) as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumourigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.
Publication Title
Novel mutations target distinct subgroups of medulloblastoma.
Sample Metadata Fields
Sex
View Samples- Homo sapiens
- 49 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Atypical teratoid/rhabdoid tumor (ATRT) is one of the most common brain tumors in infants. Although the prognosis of ATRT patients is poor, some patients respond favorably to current treatments, suggesting molecular inter-tumor heterogeneity. To investigate this further, we genetically and epigenetically analyzed a large series of human ATRTs. Three distinct molecular subgroups of ATRTs, associated with differences in demographics, tumor location, and type of SMARCB1 alterations, were identified. Whole-genome DNA and RNA sequencing found no recurrent mutations in addition to SMARCB1 that would explain the differences between subgroups. Whole-genome bisulfite sequencing and H3K27Ac chromatin-immunoprecipitation sequencing of primary tumors, however, revealed clear differences, leading to the identification of subgroup-specific regulatory networks and potential therapeutic targets.
Publication Title
Atypical Teratoid/Rhabdoid Tumors Are Comprised of Three Epigenetic Subgroups with Distinct Enhancer Landscapes.
Sample Metadata Fields
Sex, Age
View Samples- Caenorhabditis elegans
- 23 Downloadable Samples
Illumina HiSeq 2500
Description
Epigenetic inheritance contributes fundamentally to transgenerational physiology and fitness. Mechanistic understanding of RNA-mediated chromatin modification and transgenerational epigenetic inheritance, which in C. elegans can be triggered by exogenous double-stranded RNA (exo-dsRNA) or facilitated by endogenous small interfering RNAs (endo-siRNAs), has mainly been limited to the post-initiation phases of silencing. Indeed, the dynamic process by which nuclear RNAi engages a transcriptionally active target, before the repressive state is stably established, remains largely a mystery. Here we found that the onset of exo-dsRNA-induced nuclear RNAi is a transgenerational process, and that establishment requires SET-32, one of the three putative histone methyltransferases (HMTs) that are required for H3K9me3 deposition at the nuclear RNAi targets. We also performed multigenerational whole-genome analyses to examine the establishment of silencing at endogenous targets of germline nuclear RNAi. The nuclear Argonaute (AGO) protein HRDE-1 is essential for the maintenance of nuclear RNAi. Repairing a loss-of-function mutation in hrde-1 by CRISPR restored the silencing of endogenous targets in animals carrying wild type set-32. However, for numerous endogenous targets, repairing the hrde-1 mutation in a set-32;hrde-1 double mutant failed to restore their silencing states in up to 20 generations after the hrde-1 repair, using a similar genome editing approach. We found that despite a prominent role in the establishment of silencing, however, set-32 is completely dispensable for the maintenance of silencing once HRDE-1-dependent gene repression is established. Our study indicates that: 1) initiation and maintenance of siRNA-guided transcriptional repression are two distinct processes with different genetic requirements; and 2) the rate-limiting step of the establishment phase is a transgenerational, chromatin-based process. In addition, our study reveals a novel paradigm in which a heterochromatin factor primarily functions to promote the initiation of transgenerational silencing, expanding mechanistic understanding of the well-recognized role of heterochromatin in epigenetic maintenance. Overall design: 23 samples were analyzed using RNA-seq
Publication Title
C. elegans Heterochromatin Factor SET-32 Plays an Essential Role in Transgenerational Establishment of Nuclear RNAi-Mediated Epigenetic Silencing.
Sample Metadata Fields
Sex, Subject
View Samples- Drosophila melanogaster
- 6 Downloadable Samples
- Illumina HiSeq 2500
Description
SIN3 is a master transcriptional scaffold protein. SIN3 interacts with RPD3 and other accessory proteins to form a histone modifying complex. A single Sin3A gene encodes multiple isoforms of SIN3, of which SIN3 187 and SIN3 220 are the predominant isoforms. Previous studies demonstrated that SIN3 isoforms play non-redundant roles during fly development. In the current study, we sought to investigate the genes regulated by SIN3 187. Overall design: S2 cells and cells carrying a stable transgene of SIN3 187HA (SIN3 187HA cells) were treated with 0.07 µM CuSO4. CuSO4 treatment led to ectopic expression of SIN3 187HA. S2 cells were used as a control. Following induction, total mRNA was extracted. mRNA profiling of these samples were performed by deep sequencing using Illumina Hiseq2500. Three biological replicates were performed.
Publication Title
Genome-wide studies reveal novel and distinct biological pathways regulated by SIN3 isoforms.
Sample Metadata Fields
Cell line, Subject
View Samples