Molecular subgroups of medulloblastoma

Northcott, Paul A.; Dubuc, Adrian M.; Pfister, Stefan M.; Taylor, Michael D.

doi:10.1586/ern.12.66

Cited by 154 publications

(123 citation statements)

References 92 publications

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“…Human medulloblastoma (MB) can be segregated into four major categories based on gene expression patterns: Hedgehog (HH) subtype, Wnt subtype, Group 3, and Group 4 (35,36). However, they all exhibit strikingly different gene expression profiles from AT/RT (37).…”

Section: Resultsmentioning

confidence: 99%

Generation of a Mouse Model of Atypical Teratoid/Rhabdoid Tumor of the Central Nervous System through Combined Deletion of Snf5 and p53

Martı́nez

Marsh

et al. 2015

Cancer Research

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Malignant rhabdoid tumors arise in several anatomic locations and are associated with poor outcomes. In the brain, these tumors are known as atypical teratoid/rhabdoid tumors (AT/RT). While genetically engineered models for malignant rhabdoid tumors exist, none of them recapitulate AT/RT for which preclinical models remain lacking. In the majority of AT/RT, loss of heterozygosity occurs at the genetic locus SNF5 (Ini1/BAF47/Smarcb1), which functions as a subunit of the SWI/SNF chromatin-remodeling complex and a tumor suppressor in familial and sporadic malignant rhabdoid tumors. Therefore, we generated mice in which Snf5 was ablated specifically in nestin-positive and/or glial fibrillary acid protein (GFAP)-positive progenitor cells of the developing central nervous system (CNS). Snf5 ablation in nestin-positive cells resulted in early lethality that could not be rescued by loss of p53. However, Snf5 ablation in GFAP-positive cells caused a neurodegenerative phenotype exacerabated by p53 loss. Notably, these double mutants exhibited AT/RT development, associated with an earlier failure in granule neuron migration in the cerebellum, reduced neuronal projections in the hippocampus, degeneration of the corpus callosum and ataxia and seizures. Gene expression analysis confirmed that the tumors which arose in Snf5/p53 mutant mice were distinct from other neural tumors and most closely resembled human AT/RT. Our findings uncover a novel role for Snf5 in oligodendrocyte generation and survival, and they offer evidence of the first genetically engineered mouse model for AT/RT in the CNS.

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Section: Resultsmentioning

confidence: 99%

Generation of a Mouse Model of Atypical Teratoid/Rhabdoid Tumor of the Central Nervous System through Combined Deletion of Snf5 and p53

Martı́nez

Marsh

et al. 2015

Cancer Research

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“…High resolution copy number arrays and transcriptional profiling platforms have been used by several groups of investigators to subclassify MB into at least four distinct subgroups with different demographics and prognoses (27,28). It has been proposed that stratification of MBs into one of these subgroups can offer better risk assessment to patients as well as potentially guide treatment decisions.…”

Section: Resultsmentioning

confidence: 99%

“…For example, a MB with monosomy 6 as the only abnormality is consistent with the WNT pathway subgroup, which has an overall good prognosis (27,28). In contrast, the presence of an i(17)(q10), with or without MYC amplification, places the tumor into either a poor (Group 3) or intermediate (Group 4) risk category (28).…”

mentioning

confidence: 99%

Diagnostic application of high resolution single nucleotide polymorphism array analysis for children with brain tumors

et al. 2014

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Single nucleotide polymorphism (SNP) array analysis is currently used as a first tier test for pediatric brain tumors at The Children's Hospital of Philadelphia. The results from 100 consecutive patients are summarized in the present report. Eighty-seven percent of the tumors had at least one pathogenic copy number alteration. Nineteen of 56 low grade gliomas (LGGs) demonstrated a duplication in 7q34, which resulted in a KIAA1549-BRAF fusion. Chromosome band 7q34 deletions, which resulted in a FAM131B-BRAF fusion, were identified in one pilocytic astrocytoma and one dysembryoplastic neuroepithelial tumor (DNT). One ganglioglioma (GG) demonstrated a 6q23.3q26 deletion that was predicted to result in a MYB-QKI fusion. Gains of chromosomes 5, 6, 7, 11, and 20 were seen in a subset of LGGs. Monosomy 6, deletion of 9q and 10q, and an i(17)(q10) were each detected in the medulloblastomas (MBs). Deletions and regions of loss of heterozygosity that encompassed TP53, RB1, CDKN2A/B, CHEK2, NF1, and NF2 were identified in a variety of tumors, which led to a recommendation for germline testing. A BRAF p.Thr599dup or p.V600E mutation was identified by Sanger sequencing in one and five LGGs, respectively, and a somatic TP53 mutation was identified in a fibrillary astrocytoma. No TP53 hot-spot mutations were detected in the MBs. SNP array analysis of pediatric brain tumors can be combined with pathologic examination and molecular analyses to further refine diagnoses, offer more accurate prognostic assessments, and identify patients who should be referred for cancer risk assessment.

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“…Medulloblastoma is the most common malignant brain tumor in children that still has high cancer-related mortality and survivors often suffer from serious therapy-related side effects [21–23]. Arising in the cerebellum, medulloblastoma is divided into four distinct subgroups: Wnt, Shh (Sonic hedgehog), and Groups 3 and 4 [22, 24]. Tumors of the Wnt group have a fairly good prognosis, but effective therapies for the other groups have yet to be identified.…”

Section: Introductionmentioning

confidence: 99%

Beta-hairpin hydrogels as scaffolds for high-throughput drug discovery in three-dimensional cell culture

Worthington

Drake

et al. 2017

Analytical Biochemistry

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Automated cell-based high-throughput screening (HTS) is a powerful tool in drug discovery, and it is increasingly being recognized that three-dimensional (3D) models, which more closely mimic in vivo-like conditions, are desirable screening platforms. One limitation hampering the development of 3D HTS is the lack of suitable 3D culture scaffolds that can readily be incorporated into existing HTS infrastructure. We now show that β-hairpin peptide hydrogels can serve as a 3D cell culture platform that is compatible with HTS. MAX8 β-hairpin peptides can physically assemble into a hydrogel with defined porosity, permeability and mechanical stability with encapsulated cells. Most importantly, the hydrogels can then be injected under shear-flow and immediately reheal into a hydrogel with the same properties exhibited prior to injection. The post-injection hydrogels are cell culture compatible at physiological conditions. Using standard HTS equipment and medulloblastoma pediatric brain tumor cells as a model system, we show that automatic distribution of cell-peptide mixtures into 384-well assay plates results in evenly dispensed, viable MAX8-cell constructs suitable for commercially available cell viability assays. Since MAX8 peptides can be functionalized to mimic the microenvironment of cells from a variety of origins, MAX8 peptide gels should have broad applicability for 3D HTS drug discovery.

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Molecular subgroups of medulloblastoma

Cited by 154 publications

References 92 publications

Generation of a Mouse Model of Atypical Teratoid/Rhabdoid Tumor of the Central Nervous System through Combined Deletion of Snf5 and p53

Generation of a Mouse Model of Atypical Teratoid/Rhabdoid Tumor of the Central Nervous System through Combined Deletion of Snf5 and p53

Diagnostic application of high resolution single nucleotide polymorphism array analysis for children with brain tumors

Beta-hairpin hydrogels as scaffolds for high-throughput drug discovery in three-dimensional cell culture

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