Chromatin landscape of medulloblastoma reveals context dependent driver
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ABSTRACT:
PROVIDER: EGAS00001006741 | EGA |
REPOSITORIES: EGA
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Project 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. A total of 76 pediatric medulloblastoma samples were analyzed, representing 4 expression classes
2012-07-05 | E-GEOD-37418 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE33199: A mouse model of the most aggressive subgroup of human medulloblastoma [Mouse430_2] GSE33200: A mouse model of the most aggressive subgroup of human medulloblastoma [HT_MG-430_PM] Refer to individual Series
2012-02-29 | E-GEOD-33201 | biostudies-arrayexpress
Project description:DDX3X is an ATP-dependent RNA helicase. Missense mutations in DDX3X gene are known to occur in WNT, SHH subgroup medulloblastomas. The role of DDX3X in medulloblastoma biology was studied by downregulating its expression in a SHH subgroup Daoy medulloblastoma cell line. DDX3X knockdown resulted in considerable reduction in proliferation, clonogenic potential and anchorage-independent growth of the medulloblastoma cells. Transcriptome analysis was performed to delineate the molecular mechanism underlying reduction in the malignant potential of the medulloblastoma cells upon DDX3X knockdown. Exogenous expression of three DDX3X missense mutants in the DDX3X knockdown cells could restore the malignant potential of the medulloblastoma cells.
2023-03-31 | GSE201967 | GEO
Project description:Medulloblastoma could be classified into four subtypes: Wnt, Shh, Group 3, and Group 4. Subtypes of medulloblastoma have distinct epigenetic properties. We report that a chromatin regulator SMARCA4/Brg1 controls a transcriptional program that specifically required for Shh-type medulloblastoma identity and proliferation. We show that Brg1 deletion significantly inhibited tumor formation and progression in a mouse medulloblastoma model. Genomic experiments indicate that Brg1 specifically coordinates with key transcription factors including Gli1, Atoh1, and REST to regulate the expression of both oncogenes and tumor suppressors. Shh-type medulloblastoma displays distinct H3K27me3 properties. We demonstrate that Brg1 modulates activities of H3K27me3 modifiers to regulate expression of medulloblastoma genes. Brg1 is important for the growth of a human medulloblastoma cell line and Brg1-regulated pathways are conserved in human Shh-type medulloblastoma. This study reveals a novel epigenetic mechanism that controls medulloblastoma development and provides a rationale for developing subtype-specific treatment strategies.
2016-09-14 | GSE69673 | GEO
Project description:Medulloblastoma could be classified into four subtypes: Wnt, Shh, Group 3, and Group 4. Subtypes of medulloblastoma have distinct epigenetic properties. We report that a chromatin regulator SMARCA4/Brg1 controls a transcriptional program that specifically required for Shh-type medulloblastoma identity and proliferation. We show that Brg1 deletion significantly inhibited tumor formation and progression in a mouse medulloblastoma model. Genomic experiments indicate that Brg1 specifically coordinates with key transcription factors including Gli1, Atoh1, and REST to regulate the expression of both oncogenes and tumor suppressors. Shh-type medulloblastoma displays distinct H3K27me3 properties. We demonstrate that Brg1 modulates activities of H3K27me3 modifiers to regulate expression of medulloblastoma genes. Brg1 is important for the growth of a human medulloblastoma cell line and Brg1-regulated pathways are conserved in human Shh-type medulloblastoma. This study reveals a novel epigenetic mechanism that controls medulloblastoma development and provides a rationale for developing subtype-specific treatment strategies.
2016-09-14 | GSE69672 | GEO
Project description:We explore cellular heterogeneity in 28 childhood medulloblastoma (MB) (1 WNT, 9 SHH, 7 GP3 and 11 GP4) using single-cell RNA sequencing (scRNA-seq), immunohistochemistry and deconvolution of bulk transcriptomic data. Neoplastic cells are broadly clustered according to subgroup, and within subgroups discrete sample clustering is associated with chromosomal copy number variance. Each subgroup contains subpopulations exhibiting mitotic , undifferentiated and neuronal differentiated transcript profiles , corroborating other recent medulloblastoma scRNA-seq studies and identifying new subpopulations. We identify a photoreceptor-differentiated subpopulation that is predominantly found in GP3 medulloblastoma, and in SHH, a subpopulation that constitutes differentiating nodules . Deconvolution of a large transcriptomic dataset shows that neoplastic subpopulations are associated with major and minor subgroup subdivisions, for example, photoreceptor subpopulation cells are more abundant in GP3-alpha. This scRNA-seq dataset also demonstrates medulloblastoma subgroup-specific differences in the tumor microenvironment and immune landscape, and reveals an SHH nodule -associated myeloid subpopulation. Additionally, we perform scRNA-seq on genetically engineered mouse (GEM) models of GP3 and SHH medulloblastoma. These models specifically matched the corresponding human subgroup-specific neoplastic subpopulations. We provide an interactive online resource that facilitates exploration of these MB single cell datasets. Collectively, our findings advance our understanding of the neoplastic and immune landscape of the main medulloblastoma subgroups in both humans and GEM models.
2021-06-04 | GSE155446 | GEO
Project description:Recent genomic approaches have suggested the existence of multiple distinct subtypes of medulloblastoma. We studied a large cohort of medulloblastomas to determine how many subgroups of the disease exist, how they differ, and the extent of overlap between subgroups. We determined gene expression profiles and DNA copy number aberrations for 103 primary medulloblastomas. Bioinformatic tools were used for class discovery of medulloblastoma subgroups based on the most informative genes in the dataset. Immunohistochemistry for subgroup-specific ‘signature’ genes was used to determine subgroup affiliation for 294 non-overlapping medulloblastomas on two independent tissue microarrays (TMAs). Multiple unsupervised analyses of transcriptional profiles identified four distinct, non-overlapping molecular variants: WNT, SHH, Group C, and Group D. Supervised analysis of these four subgroups revealed significant subgroup-specific demographics, histology, metastatic status, and DNA copy number aberrations. Immunohistochemistry for DKK1 (WNT), SFRP1 (SHH), NPR3 (Group C), and KCNA1 (Group D) could reliably and uniquely classify formalin fixed medulloblastomas in ~98% of cases. Group C patients (NPR3 +ve tumors) exhibited a significantly diminished progression free and overall survival irrespective of their metastatic status. Our integrative genomics approach to a large cohort of medulloblastomas has identified four disparate subgroups with distinct demographics, clinical presentation, transcriptional profiles, genetic abnormalities, and clinical outcome. Medulloblastomas can be reliably assigned to subgroups through immunohistochemistry, thereby making medulloblastoma sub-classification widely available. Future research on medulloblastoma and the development of clinical trials should take into consideration these four distinct types of medulloblastoma. A total of 103 primary medulloblastoma specimens were profiled by Affymetrix exon array and gene-level analysis was performed.
2010-09-13 | E-GEOD-21140 | biostudies-arrayexpress
Project 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.
2012-07-06 | GSE37418 | GEO
Project description:We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC gene family amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this molecular group died of rapidly progressive disease post-relapse. To study this genetic interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of Trp53 function in this model produced aggressive tumors that mimicked the characteristics of relapsed human tumors with combined P53-MYC dysfunction. Restoration of p53 activity, genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53–MYC interactions which emerge at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically. Using this dataset, assignation of medulloblastoma molecular subgroup by Illumina 450k microarray was performed for diagnostic and relapsed medulloblastoma samples to compare subgroup membership at diagnosis and relapse. We investigated the DNA methylation profiles of 18 diagnostic and 22 relapsing samples (including 15 diagnostic / relapse pairs) using the Illumina 450k methylation microarray
2015-04-23 | E-GEOD-62618 | biostudies-arrayexpress
Project description:Using FACS sorting on SOX2-eGFP and MKi67-RFP mice on a Ptch1+/- background, we identified cycling& non-cycling stem cells and tumor bulk subpopulations in endpoint mouse SHH-subgroup medulloblastoma tumors, and determined their chromatin accessibility progiles to identify unique regulators of cell state.
2024-09-11 | GSE233993 | GEO