Linked-read based analysis of Medulloblastomas
Ontology highlight
ABSTRACT:
PROVIDER: EGAS00001007064 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:We report the application of single-molecule-based sequencing technology for high-throughput profiling of chromosome occupation and single cell gene expression or single nuclei chromatin accessibility in medulloblastoma tissues or cells. To further define the cellular identity at the single cell level, we characterized 26 MB tissues including 18 newly diagnosed MB tumor tissues by single cell scRNA-seq and scATAC-seq (the assay for transposase-accessible chromatin-sequencing) together with 8 previously reported MB single cell transcriptomics. The newly diagnosed MB tumors included four SHH-MBs (45,731 cells), nine G3-MBs (82,834 cells), thirteen G4 MBs (77,521 cells) with a median of 7,926 cells for scRNA-seq and 9,342 cells for scATAC-seq per MB tumor, respectively. To decipher how dynamic accessibility at the cis-regulatory elements (CREs) relates to the gene regulatory program in TCP-like cells from G3- and G4- MBs, we performed single nuclei ATAC-seq (snATAC-seq) to determine the single-cell chromatin accessibility landscape using high-quality nuclei from a set of fresh G3 and G4 MB tumors that matched with scRNA-seq. Finally, we show that gene expression with chromatin state can be read in an allele-specific manner by using single nucleotide polymorphisms. Our studies identified a human-specific intermediate progenitor population important for cerebellar neural lineage development and the growth and metastasis of aggressive MBs, highlighting potential therapeutic targets.
2022-10-08 | GSE198565 | GEO
Project description:Linked-read data from 25 medulloblastomas and their matching control. Dataset consists of 25 group 4 medulloblastomas (G4) as well as 2 sonic hedgehog medulloblastomas (SHH-MB) samples and 2 group 3 medulloblastomas.
The data consists of BAM files generated by the LongRanger pipeline developed by 10x Genomics
| EGAD00001010849 | EGA
Project description:We exploited microarrays to detail the global program of gene expression underlying normal stem cells and cancer stem cells in the cerebellum and in medulloblastomas (MBs).
2012-04-17 | GSE37316 | GEO
Project description:Medulloblastomas (MBs) are malignant pediatric brain tumors that are molecularly and clinically very heterogenous. To unravel phenotypically relevant MB subtypes, we compiled a harmonized proteome dataset of 167 MBs and integrated findings with DNA methylation and N-glycome data. Six proteome MB subtypes emerged, that could be assigned to two main molecular programs: transcription/translation (pSHHt, pWNT and pGroup3-Myc), and synapses/immunological processes (pSHHs, pGroup3 and pGroup4). Multiomic analysis revealed different conservation levels of proteome features across MB subtypes at the DNA-methylation level. Aggressive pGroup3-Myc MBs and favorable pWNT MBs were most similar in cluster hierarchies concerning overall proteome patterns but showed different protein abundances of the vincristine resistance associated multiprotein complex TriC/CCT and of N-glycan turnover associated factors. The N-glycome reflected proteome subtypes and complex-bisecting N-glycans characterized pGroup3-Myc tumors. Our results shed light on new targetable alterations in MB and set a foundation for potential immunotherapies targeting glycan structures.
2024-06-05 | PXD039319 | Pride
Project description:Medulloblastoma (MB) is the most common malignant brain tumor. MB is a cerebellar tumor that occurs mostly in children between the ages of 3-7 years but also in adults. Human MBs are classified into four subgroups: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 (G3) and G4, each of which with distinct molecular signatures. SHH MBs with MYCN amplification and TP53 mutations and G3 MBs characterized by C-MYC (MYC) overexpression in ~17% of cases from gene amplification with stem like properties, are the most aggressive and least curable with current therapeutic regimen. Using an orthotopic transplant approach, we found that enforced expression of MYCN in cerebellar granule neural progenitors (CGNPs) from 5-7 days old Trp53-null mice induced SHH MBs after transfer in the cortices or cerebella of naive recipient mice. In contrast, overexpression of MYC induced G3 MBs. Because MYCN and MYC bind to the same E-box DNA sequences, we hypothesized that the difference between MYC and MYCN-induced gene expression and tumor identity might be due to their interaction with different partners in CGNPs. In this study, we investigated the role of the Myc interacting zinc finger protein 1 (MIZ1). We found that MIZ1 binds with higher affinity to MYC than to MYCN and that MIZ1 and MYC co-occupy thousands of promoters in G3 MB. Remarkably, enforced expression of a MYC mutant (MYCV394D) that no longer binds to MIZ1 in Trp53-null CGNPs or expression of wild type MYC in CGNPs that lack functional Miz1 resulted in massive changes of the resulting tumorâ??s transcriptional program. Tumors differed from both SHH and G3 medulloblastoma and had a later time of onset compared to MYC-driven G3 medulloblastoma. Our data demonstrate that interaction of MYC with MIZ1 is required for the development of G3 medulloblastoma. ChIP-Seq experiments for Miz1, c-Myc and NMyc from murine medulloblastoma material. Either sorted tumor cells (Miz1 and c-Myc) or spheres from tumor cells (Miz1 and NMyc) were used. Input-samples were sequenced as controls. RNA-Seq from G3 medulloblastomas after restoration of Atoh1 expression.
2016-01-21 | E-GEOD-64425 | biostudies-arrayexpress
Project description:Medulloblastomas (MBs) are malignant pediatric brain tumors that are molecularly and clinically very heterogenous. To unravel phenotypically relevant MB subtypes, we compiled a harmonized proteome dataset of 167 MBs and integrated findings with DNA methylation and N-glycome data. Six proteome MB subtypes emerged, that could be assigned to two main molecular programs: transcription/translation (pSHHt, pWNT and pGroup3-Myc), and synapses/immunological processes (pSHHs, pGroup3 and pGroup4). Multiomic analysis revealed different conservation levels of proteome features across MB subtypes at the DNA-methylation level. Aggressive pGroup3-Myc MBs and favorable pWNT MBs were most similar in cluster hierarchies concerning overall proteome patterns but showed different protein abundances of the vincristine resistance associated multiprotein complex TriC/CCT and of N-glycan turnover associated factors. The N-glycome reflected proteome subtypes and complex-bisecting N-glycans characterized pGroup3-Myc tumors. Our results shed light on new targetable alterations in MB and set a foundation for potential immunotherapies targeting glycan structures. This dataset includes samples which were used for technical and biological validation of previously acquired results.
2024-06-03 | PXD048767 | Pride
Project description:Medulloblastomas (MBs) and Glioblastomas (GBMs) are high-incidence central nervous system tumors. Different origin sites and changes in the tissue microenvironment have been associated with onset and progression. Here, we describe differences between the ECM signature of these tumors. We compared the proteomic profiles of MB and GBM decellularized tumor samples among each other and their normal decellularized brain site counterparts. Our analysis reveals that 19 proteins were differentially expressed in MBs, 28 proteins in GBMs, and 11 proteins in both MBs and GBMs. Next, we validated key findings by protein tissue array with 53 MB and 55 GBM cases and evaluated the clinical relevance of the identified differentially expressed proteins through their analysis on publicly available datasets, 763 MB samples from microarray-GSE50161, and 115 GBM samples from RNAseq-TCGA. We report a shift towards a denser fibrillary ECM as well as a clear alteration in the glycoprotein signature, which influences the tumor pathophysiology.
2021-12-30 | PXD023350 | Pride
Project description:Medulloblastomas (MBs) are cerebellar tumors that can be classified into molecularly distinct subgroups that differ in pathology and prognosis. The mechanisms that underlie subgroup specification are largely unknown. While human SHH MBs express MYCN, Group3 (G3) MBs are associated with c-MYC (MYC) overexpression and often show metastasis that confers a poor prognosis. Although MYC proteins are thought to be functionally exchangeable, ectopic expression of Myc or N-myc in Trp53-/-;Cdkn2c-/- cerebellar granule neuron progenitors (GNPs) induces G3 and SHH MBs, respectively, demonstrating that each Myc protein has distinct biological properties. We now show that Myc and N-myc differ in their affinity to Miz1 and that Myc, but not N-myc, effectively recruits Miz1 to its target sites on chromatin. The interaction of Myc with Miz1 is required for the genesis of G3 MB. Myc suppresses ciliogenesis and âreprogramsâ the transcriptome of SHH-dependent GNPs to stem-like cells by repressing genes highly expressed in SHH MB via Miz1. Consistently, target genes of Myc/Miz1 are repressed in human G3 MBs but not in other MB subgroups. Collectively, the data show that the interaction of Myc with Miz1 is a defining hallmark of G3 MB development. In this study, we show that Myc and N-myc differ in their affinity for Miz1, and Myc/Miz1 interaction is required for Group3 medulloblastoma (MB). The gene expression profiles of these tumors were compared to our previously published Group3 MB model as well as SHH model of MB (Kawachi et al., 2012, Cancer Cell). Cerebellar granule neuron progenitors (GNPs) [dka220-222] from postnatal (P) 6 Math1-GFP;Trp53-/-;Cdkn2c-/-. For SHH medulloblastomas, [dka204-206] and [blm015-017 or dka050-dka051], spontaneous medulloblastomas from Cdkn2c-/-;Trp53Fl/Fl;Nestin-Cre (Kawachi et al., 2012, Cancer Cell) and Ptch1+/-;Cdkn2c-/- (Uziel et al., 2005, Genes Dev) were used, respectively. Myc- [dka201-203] and MycV394D (termed MycVD thereafter)- [bvo017-bvo023] tumors were from Trp53-/-;Cdkn2c-/- cerebella of P6-P7 pups. Myc/ÎPOZ tumors [bvo002-bvo006] were obtained from Trp5Fl/Fl;Miz1ÎPOZ/POZ;Nestin-Cre cerebella of P6-P7 pups.
2016-01-21 | E-GEOD-66093 | biostudies-arrayexpress
Project description:Medulloblastoma (MB) is a rare disease in adults. In this study we elucidated the genetic landscape and prognostic impact of genetic aberrations in a cohort of 117 adult medulloblastomas. Histological features and pathway activation were evaluated on the protein level; 14.5% showed WNT activation, 63.3% SHH activation and 22.2% were annotated to non-WNT/non-SHH-MB. Genome-wide copy number analysis was performed by molecular inversion probe array technology. MB-related genes were sequenced in WNT- and SHH-activated MBs. 79.7% of SHH-MBs showed desmoplastic/nodular, all other MBs classic histology. WNT-MBs carried oncogenic CTNNB1 mutations in 88.2% and had monosomy 6 in 52.9%. In SHH-MBs, TERT promoter mutations occurred in 97%, mutations in PTCH1 in 38.2%, SMO in 15.5%, SUFU in 7.4%, and TP53-mutations in 4.1%. 84.6% of non-WNT/non-SHH-MBs had an isochromosome 17q. A whole chromosomal aberration (WCA) signature was present in 45.1% of SHH-TP53wt-MBs and 65.4% of non-WNT/non-SHH-MBs. In 98 cases with survival data, WNT-MBs had a 5-year overall survival (OS) of 68.6%. SHH-MBs TP53-wild-type and non-WNT/non-SHH-MBs showed 5-year OS of 80.4% and 70.8%, respectively. TP53-mutant SHH-MBs represented a prognostically unfavorable entity; all patients died within 5 years. Patients with a WCA signature showed significantly increased OS (p-=-0.011 for SHH-TP53wt-MBs, p-=-0.048 for non-WNT/non-SHH-MBs).
2021-02-24 | GSE167347 | GEO
Project description:Identification of common mechanisms underlying organ development and primary tumor formation should yield new insights into tumor biology and facilitate the generation of relevant cancer models. We have developed a novel method to project the gene expression profiles of medulloblastomas (MBs)—human cerebellar tumors—onto a mouse cerebellar development sequence: postnatal days 1-60 (P1-P60). Genomically, human medulloblastomas were closest to mouse P1-P10 cerebella, and normal human cerebella were closest to mouse P30-P60 cerebella. Furthermore, metastatic MBs were highly associated with mouse P5 cerebella, suggesting that a clinically distinct subset of tumors is identifiable by molecular similarity to a precise developmental stage. Genewise, down- and up-regulated MB genes segregate to late and early stages of development, respectively. Comparable results for human lung cancer vis-a-vis the developing mouse lung suggest the generalizability of this multiscalar developmental perspective on tumor biology. Our findings indicate both a recapitulation of tissue-specific developmental programs in diverse solid tumors and the utility of tumor characterization on the developmental time axis for identifying novel aspects of clinical and biological behavior. Experiment Overall Design: Time series with technical (split aliquots) replicates.
2009-01-30 | E-GEOD-14514 | biostudies-arrayexpress