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Berlin Brandenburg

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  • Nature Publishing Group (CrossRef)  (14)
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  • 1
    In: Nature Medicine, 2014, Vol.20(12), p.1378
    Description: Despite advances in chemotherapy and radiation over the past 40 years, the outcome for children with diffuse intrinsic pontine gliomas (DIPGs) remains almost uniformly fatal, with survival of less than 12 months despite numerous trials of chemotherapy, targeted agents and radiation therapy. Recently, large genome-sequencing studies of pediatric high-grade gliomas have been carried out and have consistently identified a lysine to methionine (K27M) substitution in histones H3.1 and H3.3 in over 80% of midline high-grade gliomas and DIPGs2.
    Keywords: Tumors ; Chemotherapy ; Radiation Therapy ; Medical Research ; Epigenetics;
    ISSN: 1078-8956
    E-ISSN: 1546170X
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  • 2
    In: Nature, 2014
    Description: Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.
    Keywords: Medulloblastoma – Research ; Medulloblastoma – Health Aspects ; DNA Sequencing – Analysis ; Growth Factor Receptors – Analysis;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 3
    Language: English
    In: Nature Reviews Clinical Oncology, Nov, 2018, Vol.15(11), p.659
    Description: Comprehensive molecular characterization of infant medulloblastoma has uncovered the high degree of heterogeneity of this disease. Recent results from the SJYC07 study elegantly reveal that risk stratification can be improved if DNA methylation profiling data are incorporated into...
    Keywords: Molecular Diagnostic Techniques -- Innovations ; Gene Expression -- Health Aspects ; Pediatric Tumors -- Genetic Aspects ; Pediatric Tumors -- Development And Progression ; Pediatric Tumors -- Care And Treatment ; Medulloblastoma -- Care And Treatment ; Medulloblastoma -- Development And Progression ; Medulloblastoma -- Genetic Aspects
    ISSN: 1759-4774
    E-ISSN: 17594782
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  • 4
    In: Oncogene, 2016, Vol.35(32), p.4256-4268
    Description: Post-natal proliferation of cerebellar granule neuron precursors (CGNPs), proposed cells-of-origin for the SHH-associated subgroup of medulloblastoma (MB), is driven by Sonic Hedgehog (Shh) and Insulin-like Growth Factor (IGF) in the developing cerebellum. Shh induces the oncogene Yes-associated protein (YAP), which drives IGF2 expression in CGNPs and mouse Shh-associated medulloblastomas. To determine how IGF2 expression is regulated downstream of YAP, we carried out an unbiased screen for transcriptional regulators bound to IGF2 promoters. We report that Y-box binding protein-1 (YB-1), an onco-protein regulating transcription and translation, binds to IGF2 promoter P3. We observed that YB-1 is up-regulated across human medulloblastoma subclasses as well as in other varieties of pediatric brain tumors. Utilizing the cerebellar progenitor model for the Shh-subgroup of MB in mice, we show for the first time that YB-1 is induced by Shh in CGNPs. Its expression is YAP-dependent and it is required for IGF2 expression in CGNPs. Finally, both gain-of function and loss-of-function experiments reveal that YB-1 activity is required for sustaining CGNP and medulloblastoma cell (MBC) proliferation. Collectively, our findings describe a novel role for YB-1 in driving proliferation in the developing cerebellum and medulloblastoma cells and they identify the SHH:YAP:YB1:IGF2 axis as a powerful target for therapeutic intervention in medulloblastomas.
    Keywords: Article ; Medulloblastoma ; Sonic Hedgehog ; Hippo ; Yb1 ; Yap ; Igf2 ; Cerebellum ; Cell Cycle
    ISSN: 0950-9232
    E-ISSN: 1476-5594
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  • 5
    Language: English
    In: He, X., L. Zhang, Y. Chen, M. Remke, D. Shih, F. Lu, H. Wang, et al. 2014. “The G-protein Alpha Subunit Gsα Is A Tumor Suppressor In Sonic Hedgehog-driven Medulloblastoma.” Nature medicine 20 (9): 1035-1042. doi:10.1038/nm.3666. http://dx.doi.org/10.1038/nm.3666.
    Description: Medulloblastoma, the most common malignant childhood brain tumor, exhibits distinct molecular subtypes and cellular origins. Genetic alterations driving medulloblastoma initiation and progression remain poorly understood. Herein, we identify GNAS, encoding the G-protein Gsα, as a potent tumor suppressor gene that defines a subset of aggressive Sonic Hedgehog (Shh)-driven human medulloblastomas. Ablation of the single Gnas gene in anatomically-distinct progenitors is sufficient to induce Shh-associated medulloblastomas, which recapitulate their human counterparts. Gsα is highly enriched at the primary cilium of granule neuron precursors and suppresses Shh-signaling by regulating both the cAMP-dependent pathway and ciliary trafficking of Hedgehog pathway components. Elevation of a Gsα effector, cAMP, effectively inhibits tumor cell proliferation and progression in Gnas mutants. Thus, our gain- and loss-of-function studies identify a previously unrecognized tumor suppressor function for Gsα that acts as a molecular link across Shh-group medulloblastomas of disparate cellular and anatomical origins, illuminating G-protein modulation as a potential therapeutic avenue.
    Keywords: Medulloblastoma ; G-Protein ; Camp ; Gpcr ; Cell Lineage ; Sonic Hedgehog Signaling ; Cilia ; Cellular Origins
    ISSN: 1078-8956
    E-ISSN: 1546170X
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  • 6
    In: Nature, 2012, Vol.488(7409), p.100
    Description: Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients.
    Keywords: Cerebellar Neoplasms -- Genetics ; Genome, Human -- Genetics ; Medulloblastoma -- Genetics;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 7
    Language: English
    In: Nature neuroscience, September 2015, Vol.18(9), pp.1236-46
    Description: Over 20% of the drugs for treating human diseases target ion channels, but no cancer drug approved by the US Food and Drug Administration (FDA) is intended to target an ion channel. We found that the EAG2 (Ether-a-go-go 2) potassium channel has an evolutionarily conserved function for promoting brain tumor growth and metastasis, delineate downstream pathways, and uncover a mechanism for different potassium channels to functionally cooperate and regulate mitotic cell volume and tumor progression. EAG2 potassium channel was enriched at the trailing edge of migrating medulloblastoma (MB) cells to regulate local cell volume dynamics, thereby facilitating cell motility. We identified the FDA-approved antipsychotic drug thioridazine as an EAG2 channel blocker that reduces xenografted MB growth and metastasis, and present a case report of repurposing thioridazine for treating a human patient. Our findings illustrate the potential of targeting ion channels in cancer treatment.
    Keywords: Evolution, Molecular ; Brain Neoplasms -- Drug Therapy ; Drug Delivery Systems -- Methods ; Ether-A-Go-Go Potassium Channels -- Antagonists & Inhibitors ; Thioridazine -- Administration & Dosage
    ISSN: 10976256
    E-ISSN: 1546-1726
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  • 8
    In: Nature Genetics, 2013, Vol.46(1), p.39
    Description: Embryonal tumors with multilayered rosettes (ETMRs) are rare, deadly pediatric brain tumors characterized by high-level amplification of the microRNA cluster C19MC(1,2). We performed integrated genetic and epigenetic analyses of 12 ETMR samples and identified, in all cases, C19MC fusions to TTYH1 driving expression of the microRNAs. ETMR tumors, cell lines and xenografts showed a specific DNA methylation pattern distinct from those of other tumors and normal tissues. We detected extreme overexpression of a previously uncharacterized isoform of DNMT3B originating at an alternative promoter (3) that is active only in the first weeks of neural tube development. Transcriptional and immunohistochemical analyses suggest that C19MC-dependent DNMT3B deregulation is mediated by RBL2, a known repressor of DNMT3B (4,5). Transfection with individual C19MC microRNAs resulted in DNMT3B upregulation and RBL2 downregulation in cultured cells. Our data suggest a potential oncogenic re-engagement of an early developmental program in ETMR via epigenetic alteration mediated by an embryonic, brain-specific DNMT3B isoform.
    Keywords: Microrna -- Physiological Aspects ; Microrna -- Genetic Aspects ; Microrna -- Research ; Brain Tumors -- Risk Factors ; Brain Tumors -- Genetic Aspects ; Brain Tumors -- Research ; Gene Expression -- Physiological Aspects ; Gene Expression -- Research ; Methyltransferases -- Physiological Aspects ; Methyltransferases -- Genetic Aspects ; Methyltransferases -- Research;
    ISSN: 1061-4036
    E-ISSN: 15461718
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  • 9
    In: Nature, 2012, Vol.488(7409), p.49
    Description: Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4a. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-b signalling in Group 3, and NF-kB signalling in Group 4, suggest future avenues for rational, targeted therapy. [PUBLICATION ]
    Keywords: Carrier Proteins–Genetics ; Cerebellar Neoplasms–Classification ; Cerebellar Neoplasms–Genetics ; Cerebellar Neoplasms–Metabolism ; Child–Genetics ; DNA Copy Number Variations–Genetics ; Gene Duplication–Genetics ; Genes, Myc–Genetics ; Genome, Human–Genetics ; Genomic Structural Variation–Metabolism ; Genomics–Classification ; Hedgehog Proteins–Genetics ; Humans–Metabolism ; Medulloblastoma–Metabolism ; Medulloblastoma–Genetics ; Medulloblastoma–Genetics ; Nf-Kappa B–Genetics ; Nerve Tissue Proteins–Metabolism ; Oncogene Proteins, Fusion–Genetics ; Proteins–Genetics ; Signal Transduction–Genetics ; Transforming Growth Factor Beta–Genetics ; Translocation, Genetic–Genetics ; Genes ; Genomics ; Genomes ; Carrier Proteins ; Hedgehog Proteins ; Nf-Kappa B ; Nerve Tissue Proteins ; Oncogene Proteins, Fusion ; Pvt1 Long-Non-Coding RNA, Human ; Proteins ; Shh Protein, Human ; Sncaip Protein, Human ; Transforming Growth Factor Beta;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 10
    In: Nature Genetics, 2015
    Description: DNA replication-associated mutations are repaired by two components: polymerase proofreading and mismatch repair. The mutation consequences of disruption to both repair components in humans are not well studied. We sequenced cancer genomes from children with inherited biallelic mismatch repair deficiency (bMMRD). High-grade bMMRD brain tumors exhibited massive numbers of substitution mutations (〉250/Mb), which was greater than all childhood and most cancers (〉7,000 analyzed). All ultra-hypermutated bMMRD cancers acquired early somatic driver mutations in DNA polymerase ɛ or δ. The ensuing mutation signatures and numbers are unique and diagnostic of childhood germ-line bMMRD (P 〈 10(-13)). Sequential tumor biopsy analysis revealed that bMMRD/polymerase-mutant cancers rapidly amass an excess of simultaneous mutations (∼600 mutations/cell division), reaching but not exceeding ∼20,000 exonic mutations in 〈6 months. This implies a threshold compatible with cancer-cell survival. We suggest a new mechanism of cancer progression in which mutations develop in a rapid burst after ablation of replication repair.
    Keywords: Base Pair Mismatch ; DNA Mismatch Repair ; Brain Neoplasms -- Genetics ; DNA Replication -- Genetics;
    ISSN: 1061-4036
    E-ISSN: 15461718
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