Heterogenous radiomics patterns are associated with poor survivals and dysregulated pathways in medulloblastoma
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ABSTRACT:
PROVIDER: PRJNA636196 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11885100_1.fastq.gz | Fastqsanger.gz | |||
| SRR11885100_2.fastq.gz | Fastqsanger.gz | |||
| SRR11885101_1.fastq.gz | Fastqsanger.gz | |||
| SRR11885101_2.fastq.gz | Fastqsanger.gz | |||
| SRR11885102_1.fastq.gz | Fastqsanger.gz |
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Project description:Background. To develop a radiomics signature for predicting overall survival (OS) and progression-free survival (PFS) in patients with medulloblastoma (MB), and to investigate the incremental prognostic value and underlying biological pathways of the radiomics signature.Methods. A radiomics signature was constructed based on five magnetic resonance (MR) sequences (T1, T1c, T2, FLAIR and ADC) from a training cohort (n = 83) using LASSO-Cox model. Association between the signature and survival was evaluated on a testing cohort (n = 83). Incremental prognostic value of the signature beyond clinicomolecular factors was assessed with respect to calibration, discrimination, reclassification and clinical usefulness by a radiomics-clinicomolecular nomogram. Key pathways associated with the signature were identified. Prognostic value of pathway genes was assessed in a public TCGA cohort.Results. The radiomics signature was significantly associated with OS/PFS, independent from clinicomolecular factors. The radiomics-clinicomolecular nomogram predicted OS (C-index 0.762) and PFS (C-index 0.697) better than either the radiomics signature (C-index: OS: 0.649; PFS: 0.593) or the clinicomolecular nomogram (C-index: OS: 0.725; PFS: 0.691) only, with a better calibration and classification accuracy (net reclassification improvement: OS: 0.298, P = 0.022; PFS: 0.252, P = 0.026). Nine pathways were significantly correlated with the radiomics signature. Average expression value of pathway genes achieved significant risk stratification in public cohort (log-rank P = 0.016). Conclusion. This study demonstrated radiomics signature was an independent prognostic marker and offered incremental value over clinicomolecular factors in OS/PFS predictions for MB patients. The signature was associated with dysregulated pathways affecting patient prognosis in MB.
2020-06-01 | GSE151519 | GEO
Project description:<p>Medulloblastoma is a heterogenous disease made up of at least four distinct subtypes of disease which appear to exploit and disrupt naturally occurring developmental pathways of cellular growth and hindbrain development. To better understand the driver mutations of this disease, we performed whole genome sequencing of 37 medulloblastomas and the corresponding normal DNA of the 37 affected children treated at St. Jude Children's Research Hospital. We have found several novel mutations which appear subtype specific. These mutations were checked for frequency in a separate tumor cohort of 56 children with medulloblastoma, also treated on the St. Jude Medulloblastoma 2003 trial, and were tested in several animal models of medulloblastoma for proof of oncogenic potential.</p>
| phs000409 | dbGaP
Project description:Integrative Genomic Analysis of Medulloblastoma Identifies a Molecular Subgroup That Drives Poor Clinical Outcome
| PRJNA834075 | ENA
Project description:Medulloblastoma is a highly aggressive pediatric brain tumor, in which expression of the pluripotency factor OCT4 has been recently correlated with poor patient survival. However, the contribution of OCT4 transcript variants to tumor aggressiveness is still poorly understood. In this study, we found that transcripts encoding OCT4A, but not OCT4B or OCT4B1, were significantly correlated with LIN28A expression, which encodes another well-known pluripotency factor. LIN28A was found to specifically bind OCT4A transcripts and interact with poly(A) binding protein and RNA helicase A in polysomal fractions of medulloblastoma cells, favoring increased OCT4A protein levels in these cells. Medulloblastoma cells stably overexpressing OCT4A displayed significantly enhanced clonogenic activity, tumorsphere generation and invasion capability, as well as increased tumorigenicity. In an orthotopic metastatic model of medulloblastoma, OCT4A overexpressing cells generated more developed, aggressive and infiltrative tumors, with tumor-bearing mice attaining advanced metastatic disease and shorter survival rates. Pro-oncogenic effects of OCT4A were found to be expression-level dependent and accompanied by distinct subchromosomal aberrations and differential expression of newly discovered, still poorly characterized, non-coding RNAs. Altogether, our findings support the relevance of pluripotency-related factors in the aggravation of medulloblastoma traits classically associated with poor clinical outcome, and underscore the prognostic and therapeutic value of OCT4A in this challenging type of pediatric brain cancer. Total RNA of 2-3 clones of each cell line (Control and OCT4A overexpression) was extracted with the RNeasy Mini kit (Qiagen), following the manufacturerâs protocol. Gene expression profiling was carried out independently for each sample using Affymetrix GeneChip® Human Gene 2.0 ST whole-transcript arrays (Affymetrix, Santa Clara, CA, USA). The quality control and normalization of data were processed by Affymetrix® Expression Console Software (Affymetrix). Differentially expressed genes were identified with the One-Way ANOVA, with a p-value cutoff of 0.05, using Transcriptome Analysis Console v3.0 (Affymetrix).
2016-02-17 | E-GEOD-77947 | biostudies-arrayexpress
Project description:Medulloblastoma, the most common malignant pediatric brain tumour, disseminates by shedding cells into the cerebrospinal fluid, which then re-implant to cover the surface of the brain and spinal cord. Metastases are a very poor prognostic sign at presentation and are usually lethal at recurrence. Mechanisms driving dissemination have been described in the bulk primary tumour, with the underlying assumption that primary tumour and metastases are biologically similar. Here we show that in both mouse and human medulloblastoma, multiple metastases from a single animal are extremely similar, but are genetically highly divergent from the primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted sub-clone of the primary tumour, suggesting that only rare cells within the primary tumour have the ability to metastasize. Failure to account for the bicompartmental nature of primary and metastatic medulloblastoma represents a major barrier to the development of effective targeted therapies. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from cryopreserved human medulloblastoma tissue samples. Copy number analysis of Affymetrix SNP6 arrays was performed for 17 pediatric medulloblastoma samples. Samples comprise a series of 7 patient-matched primary/metastatic cases.
2011-12-09 | E-GEOD-34280 | biostudies-arrayexpress
Project description:Decoding Heterogenous Single-cell Perturbation Responses
| PRJNA1039796 | ENA
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:Little is known about the genetic regulation of medulloblastoma dissemination, but metastatic medulloblastoma is highly associated with poor outcome. We obtained expression profiles of 23 primary medulloblastomas clinically designated as either metastatic (M+) or non-metastatic (M0) and identified 85 genes whose expression differed significantly between classes. Using a class prediction algorithm based on these genes and a leave-one-out approach, we assigned sample class to these tumors (M+ or M0) with 72% accuracy and to four additional independent tumors with 100% accuracy. We also assigned the metastatic medulloblastoma cell line Daoy to the metastatic class. Notably, platelet-derived growth factor receptor alpha (PDGFRA) and members of the downstream RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway are upregulated in M+ tumors. Immunohistochemical validation on an independent set of tumors shows significant overexpression of PDGFRA in M+ tumors compared to M0 tumors. Using in vitro assays, we show that platelet-derived growth factor alpha (PDGFA) enhances medulloblastoma migration and increases downstream MAP2K1 (MEK1), MAP2K2 (MEK2), MAPK1 (p42 MAPK) and MAPK3 (p44 MAPK) phosphorylation in a dose-dependent manner. Neutralizing antibodies to PDGFRA blocks MAP2K1, MAP2K2 and MAPK1/3 phosphorylation, whereas U0126, a highly specific inhibitor of MAP2K1 and MAP2K2, also blocks MAPK1/3. Both inhibit migration and prevent PDGFA-stimulated migration. These results provide the first insight into the genetic regulation of medulloblastoma metastasis and are the first to suggest a role for PDGFRA and the RAS/MAPK signaling pathway in medulloblastoma metastasis. Inhibitors of PDGFRA and RAS proteins should therefore be considered for investigation as possible novel therapeutic strategies against medulloblastoma. Keywords: other
2003-07-16 | GSE468 | 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