8c314c38-f945-47ab-a553-eb6f5695a83e - samples
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ABSTRACT:
PROVIDER: EGAD00001004347 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:We analyzed alternative splicing with Shh medulloblastoma. This dataset contains bam files of whole genome sequencing from 4 cases. Genomic DNA was isolated from both tumor and matched control specimens. We performed whole genome sequence on Illumina Hiseq.
| EGAS00001003220 | EGA
Project description:Alternative pre-mRNA splicing critically contributes to the generation of protein variety in a tissue- and development-specific manner. Alterations in the normal pathways of alternative splicing (AS) have been associated with the growth and maintenance of several tumour types, and have been indicated as candidate bio-markers of tumour progression, metastasis and patient survival. In this study we applied genome-wide exon array technology to investigate AS events that may distinguish between human medulloblastoma and normal cerebellum. We initially investigated gene-level expression profiles to identify samples expressing gene signatures characteristic of previously described MB molecular subgroups. 3 medulloblastomas significantly over-expressed genes typically belonging to the Shh signalling pathway or associated with a granule cell progenitor status and were therefore classified as Shh-activated tumours (MB1). The remaining tumour samples were grouped together as medulloblastoma subset 2 (MB2). We then applied the Splicing Index algorithm and identified 1260 unique genes containing at least one candidate exon whose inclusion rate differed between different sample subgroups. Following the analysis of candidate event expression plots and gene structure annotation, we selected 14 examples of differential splicing of cassette exons and successfully validated 11 of them by semi-quantitative RT-PCR in a selection of the initial sample-set and subsequently in an independent set of 10 normal cerebellum and 20 medulloblastoma samples. Through the analysis of AS pathway in in vitro cultures of cerebellar granule cell progenitors (the putative cell of origin of least a subset of medulloblastomas), we showed that medulloblastoma-associated AS patterns could be indicative of a normal cerebellar undifferentiated phenotype and suggested that activation of oncogenic pathways during the development of the cerebellum may lead to a failure of neuronal differentiation also through the disruption of AS programs.
2011-01-01 | E-MTAB-292 | biostudies-arrayexpress
Project description:Genomic rearrangements typically occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving chromosome shattering and reshuffling ('chromothripsis'), for which no genetic basis has yet been described. Whole-genome sequencing of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome) revealed massive, complex rearrangements resulting from chromothripsis. Integrating TP53 status with genomic rearrangement data in additional medulloblastomas revealed a striking association between TP53 mutation and chromothripsis in SHH-MBs. Unexpectedly, five seemingly sporadic SHH-MB patients with chromothripsis harbored TP53 germline mutations – findings relevant for clinical management. Analysis of additional tumor entities substantiated a link between TP53 mutation and chromothripsis, beyond general genomic instability. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings implicate p53 in the initiation of, or cellular reaction to, chromothripsis – a novel role for the 'guardian of the genome'. The DNA copy-number profiles of 11 primary medulloblastoma samples were analyzed on the Affymetrix Mapping250K Nsp array, together with data from 70 primary samples taken from GSE21140. Data from diploid reference samples were taken from GSE9222. Additionally, DNA copy-number profiles for 19 additional medulloblastoma samples were generated on the Affymetrix SNP6 platform with matched blood samples.
2012-01-20 | E-GEOD-34258 | biostudies-arrayexpress
Project description:Here we present the case of adult medulloblastoma with minimal chromosomal rearrangements but Shh expression profile and IDH1 mutation. Data presented here are NanoString analyses of two biopsies of adult patient with a medulloblastoma which was classified as a Shh subtype Analyses were performed on 2 archival specimens of medulloblastoma, WHO Grade IV, seen at the Department of Pathology, Massachusetts General Hospital in 2007.
2013-01-01 | E-GEOD-43123 | biostudies-arrayexpress
Project description:Medulloblastoma, the most common malignant pediatric brain tumor, is highly heterogeneous with distinct molecular subtypes and cellular origins. Although current treatments improve survival rates, patients suffer severe treatment-related side effects and often relapse of tumors carrying resistance mutations, underscoring an urgent need for alternative targeted therapies. Currently, the genetic alterations underlying this disease are not fully understood. Here we identify GNAS, encoding the G-protein Gs-alpha, as a potent tumor suppressor gene in medulloblastoma. GNAS specifically defines a subset of aggressive Sonic Hedgehog (Shh)-group medulloblastomas. Gnas loss-of-function in distinct lineage progenitors of the developing hindbrain suffices to initiate medulloblastoma. We find that Gs-alpha is highly enriched at primary cilia of granule neuron precursors and suppresses Shh signaling not only by regulating classic cAMP-dependent pathway but also controlling ciliary trafficking of Smoothened. Concurrent cAMP elevation and Smoothened inhibition robustly arrests tumor cell growth in Gnas mutants. We further reveal oligodendrocyte progenitors as a novel cellular origin for anatomically-distinct Shh-associated medulloblastomas. Together, we identify a previously unrecognized tumor suppressor function of Gs-alpha in medulloblastoma partially mediated through inhibiting Shh signaling, and uncover Gs-alpha as a molecular link across disparate cells of origin among Shh-group medulloblastomas, pointing to G- protein modulation as a potential therapeutic avenue. Transgenic medulloblastoma mouse models were analyzed by Affymetrix Mouse Gene 1.1 ST Array in order to determine their molecular subgroup. Tumors extracted from hGFAP:GnasCKO and Oligo1:GnasCKO transgenic mice were analyzed in 8 replicates each, together with normal mouse cerebellum.
2014-08-24 | E-GEOD-60417 | biostudies-arrayexpress
Project description:Medulloblastoma, the most common malignant pediatric brain tumor, is highly heterogeneous with distinct molecular subtypes and cellular origins. Although current treatments improve survival rates, patients suffer severe treatment-related side effects and often relapse of tumors carrying resistance mutations, underscoring an urgent need for alternative targeted therapies. Currently, the genetic alterations underlying this disease are not fully understood. Here we identify GNAS, encoding the G-protein Gs-alpha, as a potent tumor suppressor gene in medulloblastoma. GNAS specifically defines a subset of aggressive Sonic Hedgehog (Shh)-group medulloblastomas. Gnas loss-of-function in distinct lineage progenitors of the developing hindbrain suffices to initiate medulloblastoma. We find that Gs-alpha is highly enriched at primary cilia of granule neuron precursors and suppresses Shh signaling not only by regulating classic cAMP-dependent pathway but also controlling ciliary trafficking of Smoothened. Concurrent cAMP elevation and Smoothened inhibition robustly arrests tumor cell growth in Gnas mutants. We further reveal oligodendrocyte progenitors as a novel cellular origin for anatomically-distinct Shh-associated medulloblastomas. Together, we identify a previously unrecognized tumor suppressor function of Gs-alpha in medulloblastoma partially mediated through inhibiting Shh signaling, and uncover Gs-alpha as a molecular link across disparate cells of origin among Shh-group medulloblastomas, pointing to G- protein modulation as a potential therapeutic avenue. Purpose: To known the gene expression profile of Medulloblastoma which drived by Gnas mutation Methods: mRNAs isolated from the cerebellum of control and Gnas mutants Results:Upregulation of Shh Signaling components in tumors Conclusions: The deletion of Gnas in hGFAP and Olig1 possitive cells result in substantial upregulation of shh signaling and formation of Medulloblastoma cerebellum mRNA profiles of 3 60-day old wild type (Ctrl) and 8 Olig1Cre driven Gsa conditional knockout or 8 hGFAPCre driven conditional knockout mice were generated by deep sequencing using Illumina Hiseq2000
2014-08-24 | E-GEOD-60415 | biostudies-arrayexpress
Project description:Here we present the case of adult medulloblastoma with minimal chromosomal rearrangements. Data presented here are aCGH analyses of two biopsies of adult patient with a medulloblastoma which was classified as a Shh subgroup. Analyses were performed on 2 archival specimens of medulloblastoma, WHO Grade IV, seen at the Department of Pathology, Massachusetts General Hospital from 2007. This Series represents the CGH part of the study.
2013-01-01 | E-GEOD-41990 | biostudies-arrayexpress
Project description:Medulloblastoma, the most common malignant pediatric brain tumor, is highly heterogeneous with distinct molecular subtypes and cellular origins. Although current treatments improve survival rates, patients suffer severe treatment-related side effects and often relapse of tumors carrying resistance mutations, underscoring an urgent need for alternative targeted therapies. Currently, the genetic alterations underlying this disease are not fully understood. Here we identify GNAS, encoding the G-protein Gs-alpha, as a potent tumor suppressor gene in medulloblastoma. GNAS specifically defines a subset of aggressive Sonic Hedgehog (Shh)-group medulloblastomas. Gnas loss-of-function in distinct lineage progenitors of the developing hindbrain suffices to initiate medulloblastoma. We find that Gs-alpha is highly enriched at primary cilia of granule neuron precursors and suppresses Shh signaling not only by regulating classic cAMP-dependent pathway but also controlling ciliary trafficking of Smoothened. Concurrent cAMP elevation and Smoothened inhibition robustly arrests tumor cell growth in Gnas mutants. We further reveal oligodendrocyte progenitors as a novel cellular origin for anatomically-distinct Shh-associated medulloblastomas. Together, we identify a previously unrecognized tumor suppressor function of Gs-alpha in medulloblastoma partially mediated through inhibiting Shh signaling, and uncover Gs-alpha as a molecular link across disparate cells of origin among Shh-group medulloblastomas, pointing to G- protein modulation as a potential therapeutic avenue. We isolated genomic DNAs from the cerebellum of adult wildtype mice and tumor tissue from individual GFAP-Gnas or Olig1-Gnas mutants and performed the Copy number variation analysis.
2014-08-24 | E-GEOD-60416 | biostudies-arrayexpress
Project description:Medulloblastoma is the most common malignant pediatric brain tumor, and mechanisms underlying its development are poorly understood. We identified recurrent amplification of the miR-17/92 polycistron proto-oncogene in 6% of pediatric medulloblastomas by high-resolution single-nucleotide polymorphism genotyping arrays and subsequent interphase fluorescence in situ hybridization on a human medulloblastoma tissue microarray. Profiling the expression of 427 mature microRNAs (miRNA) in a series of 90 primary human medulloblastomas revealed that components of the miR-17/92 polycistron are the most highly up-regulated miRNAs in medulloblastoma. Expression of miR-17/92 was highest in the subgroup of medulloblastomas associated with activation of the sonic hedgehog (Shh) signaling pathway compared with other subgroups of medulloblastoma. Medulloblastomas in which miR-17/92 was up-regulated also had elevated levels of MYC/MYCN expression. Consistent with its regulation by Shh, we observed that Shh treatment of primary cerebellar granule neuron precursors (CGNP), proposed cells of origin for the Shh-associated medulloblastomas, resulted in increased miR-17/92 expression. In CGNPs, the Shh effector N-myc, but not Gli1, induced miR-17/92 expression. Ectopic miR-17/92 expression in CGNPs synergized with exogenous Shh to increase proliferation and also enabled them to proliferate in the absence of Shh. We conclude that miR-17/92 is a positive effector of Shh-mediated proliferation and that aberrant expression/amplification of this miR confers a growth advantage to medulloblastomas. A total of 90 primary medulloblastoma specimens were profiled by Affymetrix exon array and gene-level analysis was performed.
2010-04-14 | E-GEOD-21166 | biostudies-arrayexpress
Project description:Medulloblastoma, the most common malignant pediatric brain tumor, is highly heterogeneous with distinct molecular subtypes and cellular origins. Although current treatments improve survival rates, patients suffer severe treatment-related side effects and often relapse of tumors carrying resistance mutations, underscoring an urgent need for alternative targeted therapies. Currently, the genetic alterations underlying this disease are not fully understood. Here we identify GNAS, encoding the G-protein Gs-alpha, as a potent tumor suppressor gene in medulloblastoma. GNAS specifically defines a subset of aggressive Sonic Hedgehog (Shh)-group medulloblastomas. Gnas loss-of-function in distinct lineage progenitors of the developing hindbrain suffices to initiate medulloblastoma. We find that Gs-alpha is highly enriched at primary cilia of granule neuron precursors and suppresses Shh signaling not only by regulating classic cAMP-dependent pathway but also controlling ciliary trafficking of Smoothened. Concurrent cAMP elevation and Smoothened inhibition robustly arrests tumor cell growth in Gnas mutants. We further reveal oligodendrocyte progenitors as a novel cellular origin for anatomically-distinct Shh-associated medulloblastomas. Together, we identify a previously unrecognized tumor suppressor function of Gs-alpha in medulloblastoma partially mediated through inhibiting Shh signaling, and uncover Gs-alpha as a molecular link across disparate cells of origin among Shh-group medulloblastomas, pointing to G- protein modulation as a potential therapeutic avenue. Purpose: To known the gene expression profile of Medulloblastoma which drived by Gnas mutation Methods: mRNAs isolated from the cerebellum of control and Gnas mutants Results:Upregulation of Shh Signaling components in tumors Conclusions: The deletion of Gnas in hGFAP and Olig1 possitive cells result in substantial upregulation of shh signaling and formation of Medulloblastoma
2014-08-24 | GSE60415 | GEO