Integrative Genomic Analysis of Medulloblastoma Identifies a Molecular Subgroup That Drives Poor Clinical Outcome
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PROVIDER: PRJNA834075 | ENA |
REPOSITORIES: ENA
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Project description:Medulloblastomas are heterogeneous tumors that collectively represent the most common malignant brain tumor in children. To understand the molecular characteristics underlying their heterogeneity and to identify whether such characteristics represent risk factors for patients with this disease, we performed an integrated genomic analysis of a large series of primary tumors. Identified are six molecular subgroups of medulloblastoma, each with a unique combination of numerical and structural chromosomal aberrations that globally influence mRNA and miRNA expression. We reveal the relative contribution of each subgroup to clinical outcome as a whole and show that a previously unidentified molecular subgroup, characterized genetically by c-MYC copy number gains and transcriptionally by enrichment of photoreceptor pathways and increased miR-183-96-182 expression, is associated with significantly lower rates of event-free and overall survivals. Our results detail the complex genomic heterogeneity of medulloblastomas and identify a previously unrecognized molecular subgroup with poor clinical outcome for which more effective therapeutic strategies should be developed.
2022-05-03 | GSE202043 | GEO
Project description:Medulloblastomas are heterogeneous tumors that collectively represent the most common malignant brain tumor in children. To understand the molecular characteristics underlying their heterogeneity and to identify whether such characteristics represent risk factors for patients with this disease, we performed an integrated genomic analysis of a large series of primary tumors. Identified are six molecular subgroups of medulloblastoma, each with a unique combination of numerical and structural chromosomal aberrations that globally influence mRNA and miRNA expression. We reveal the relative contribution of each subgroup to clinical outcome as a whole and show that a previously unidentified molecular subgroup, characterized genetically by c-MYC copy number gains and transcriptionally by enrichment of photoreceptor pathways and increased miR-183-96-182 expression, is associated with significantly lower rates of event-free and overall survivals. Our results detail the complex genomic heterogeneity of medulloblastomas and identify a previously unrecognized molecular subgroup with poor clinical outcome for which more effective therapeutic strategies should be developed.
2022-07-10 | GSE207762 | GEO
Project description:Integrative Genomic Analysis of Medulloblastoma Identifies a Molecular Subgroup That Drives Poor Clinical Outcome [DNA copy number]
| PRJNA857031 | ENA
Project description:Epigenetic blueprint identifies poor outcome and hypomethylating agent-responsive T-ALL subgroup
| PRJNA615905 | ENA
Project description: Not available
| S-EPMC3082983 | biostudies-literature
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:Ptch+/- mice, which are predisposed to SHH subgroup medulloblastoma, were mutagenised using the Sleeping Beauty transposon to identify genes which increase the frequency of medulloblastoma formation. Gene expression in tumours was assessed both to investigate their relationship to human subgroup tumours, and to identify genes where expression was altered by mutagenesis.
2013-07-09 | GSE43994 | GEO
Project description:Ptch+/- mice, which are predisposed to SHH subgroup medulloblastoma, were mutagenised using the Sleeping Beauty transposon to identify genes which increase the frequency of medulloblastoma formation. Gene expression in tumours was assessed both to investigate their relationship to human subgroup tumours, and to identify genes where expression was altered by mutagenesis. Total RNA isolated from tumours induced by SB mutagenesis were compared to normal cerebellum, tumours induced witout SB mutagenesis, and tumours from a distinct model of disease (GTML).
2013-07-09 | E-GEOD-43994 | biostudies-arrayexpress
Project description:Medulloblastoma, the most common malignant pediatric brain tumour is currently treated with non-specific cytotoxic therapies including surgery, whole brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, prior attempts to identify targets for therapy have been underpowered due to small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1087 unique medulloblastomas. SCNAs are more common than SNVs in medulloblastoma, and are predominantly subgroup enriched. The most common region of focal copy number gain is a tandem duplication of the Parkinson's disease gene SNCAIP, which is exquisitely restricted to Subgroup 4alpha. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1 that arise through localized chromosomal shattering (topochromothripsis) are restricted to Group 3 tumours. Numerous actionable SCNAs, including recurrent events targeting TGFbeta signaling in Group 3, and NF-kappaB signaling in Group 4 suggest future avenues for rational, targeted therapy This SuperSeries is composed of the SubSeries listed below.
2012-07-27 | GSE37385 | GEO
Project description:Purpose Integrated genomics approaches have identified at least four distinct biological variants in medulloblastoma: WNT, SHH, group C, and group D. Non-WNT/Non-SHH tumors are associated with metastatic dissemination and an unfavorable prognosis. Additional markers may enhance outcome prediction in Non-WNT/Non-SHH medulloblastomas. Experimental Design We combined transcriptomic and DNA copy-number analyses for 64 primary medulloblastomas. Bioinformatic tools were applied to discover marker genes of molecular variants. Differentially expressed transcripts were evaluated for prognostic value in the screening cohort. Immunopositivity for FSTL5 was correlated with molecular and prognostic subgroups for 235 non-overlapping medulloblastoma samples on two independent tissue microarrays (TMA). Results Unsupervised clustering analyses of transcriptome profiles confirmed four distinct molecular variants. Stable subgroup separation was achieved using only the 300 most varying transcripts. Specific distributions of clinical and molecular characteristics were noted for each cluster. Distinct expression patterns of FSTL5 in each molecular subgroup were confirmed by quantitative real-time PCR. Immunopositivity of FSTL5 identified a large cohort of patients (84 of 235 patients; 36%) at high risk for relapse and death. Importantly, over 50% of Non-WNT/Non-SHH tumors displayed FSTL5 negativity, delineating a large patient cohort with an excellent prognosis who would be considered intermediate/high-risk based on current molecular subtyping. Conclusions Comprehensive analyses of transcriptomic and genetic alterations delineate four distinct variants of medulloblastoma. The addition of FSTL5 immunohistochemistry to existing molecular stratification schemes can effectively identify those Non-WNT/Non-SHH tumors with a poor outcome. Immunohistochemical staining for FSTL5 could be a high-quality and practical tool for stratification and prognostication in future clinical trials of medulloblastoma. Whole-genome transcriptional profiling of human medulloblastomas. Subgrouping based on mRNA expression profiles. Fresh frozen tumor material was collected during tumor resection. Dye-swap design used for expression profiling. Reference was a pool of normal cerebellum tissue from 24 donors. Gene expression profiles illustrate distinct expression pattern at diagnosis. This submission represents the gene expression component of the study.
2011-07-01 | E-GEOD-28245 | biostudies-arrayexpress