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  • 1
    Keywords: CANCER ; transcription ; COMPLEX ; MUTATIONS ; STEM-CELLS ; MOUSE MODEL ; histone deacetylase inhibitor ; RETINOIC ACID ; DISTINCT SUBGROUPS ; DRIVEN MEDULLOBLASTOMA
    Abstract: The unexpectedly high frequency and universality of alterations to the chromatin machinery is one of the most striking themes emerging from the current deluge of cancer genomics data. Medulloblastoma (MB), a malignant pediatric brain tumor, is no exception to this trend, with a wealth of recent studies indicating multiple alterations at all levels of chromatin processing. MB is typically now regarded as being composed of four major molecular entities (WNT, SHH, Group 3 and Group 4), which vary in their clinical and biological characteristics. Similarities and differences across these subgroups are also reflected in the specific chromatin modifiers that are found to be altered in each group, and each new cancer genome sequence or microarray profile is adding to this important knowledge base. These data are fundamentally changing our understanding of tumor developmental pathways, not just for MB but also for cancer as a whole. They also provide a new class of targets for the development of rational, personalized therapeutic approaches. The mechanisms by which these chromatin remodelers are dysregulated in MB, and the consequences both for future basic research and for translation to the clinic, will be examined here.
    Type of Publication: Journal article published
    PubMed ID: 23432644
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  • 2
    Keywords: brain ; IN-VIVO ; NEURITE OUTGROWTH ; INDEPENDENT PROGNOSTIC MARKER ; STEM-CELL ; DISTINCT SUBGROUPS ; Pilocytic astrocytoma ; GENETIC PROFILES ; POSTERIOR-FOSSA EPENDYMOMA ; IMMUNOHISTOCHEMICAL EXPRESSION
    Abstract: The CD24 glycoprotein is a mediator of neuronal proliferation, differentiation and immune suppression in the normal CNS, and a proposed cancer biomarker in multiple peripheral tumor types. We performed a comparative analysis of CD24 gene expression in a large cohort of pediatric and adult brain tumors (n = 813), and further characterized protein expression in tissue sections (n = 39), primary brain tumor cultures (n = 12) and a novel orthotopic group 3 medulloblastoma xenograft model. Increased CD24 gene expression was demonstrated in ependymomas, medulloblastomas, anaplastic astrocytomas and glioblastomas, although medulloblastomas displayed higher expression than all other tumor entities. Preferential expression of CD24 in medulloblastomas was confirmed at protein level by immunostaining and computerized image analysis of cryosections. Morphologies and immunophenotyping of CD24(+) cells in tissue sections tentatively suggested disparate functions in different tumor subsets. Notably, protein staining of medulloblastoma cells was associated with prominent cytoplasmic and membranous granules, enabling rapid and robust identification of medulloblastoma cells in clinical tissue samples, as well as in experimental model systems. In conclusion, our results implicate CD24 as a clinically and experimentally useful medulloblastoma immunomarker. Although our results encourage further functional studies of CD24 as a potential molecular target in subsets of brain tumors, the promiscuous expression of CD24 in vivo highlights the importance of specificity in the future design of such targeted treatment.
    Type of Publication: Journal article published
    PubMed ID: 25820321
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  • 3
    Keywords: SIGNAL-TRANSDUCTION ; ACUTE MYELOID-LEUKEMIA ; NEURAL STEM-CELLS ; DISTINCT SUBGROUPS ; ONCOGENIC MUTATIONS ; MAPK PATHWAY ACTIVATION ; HUMAN GLIOBLASTOMA ; NOONAN-SYNDROME ; MUTATIONAL PROCESSES ; CANCER GENOMES
    Abstract: Pilocytic astrocytoma, the most common childhood brain tumor, is typically associated with mitogen-activated protein kinase (MAPK) pathway alterations. Surgically inaccessible midline tumors are therapeutically challenging, showing sustained tendency for progression and often becoming a chronic disease with substantial morbidities. Here we describe whole-genome sequencing of 96 pilocytic astrocytomas, with matched RNA sequencing (n = 73), conducted by the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. We identified recurrent activating mutations in FGFR1 and PTPN11 and new NTRK2 fusion genes in non-cerebellar tumors. New BRAF-activating changes were also observed. MAPK pathway alterations affected all tumors analyzed, with no other significant mutations identified, indicating that pilocytic astrocytoma is predominantly a single-pathway disease. Notably, we identified the same FGFR1 mutations in a subset of H3F3A-mutated pediatric glioblastoma with additional alterations in the NF1 gene. Our findings thus identify new potential therapeutic targets in distinct subsets of pilocytic astrocytoma and childhood glioblastoma.
    Type of Publication: Journal article published
    PubMed ID: 23817572
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  • 4
    Keywords: COLORECTAL-CANCER ; ACUTE LYMPHOBLASTIC-LEUKEMIA ; STEM-CELLS ; medulloblastoma ; GLIOBLASTOMA ; GENE-EXPRESSION SIGNATURE ; DISTINCT SUBGROUPS ; ISLAND METHYLATOR PHENOTYPE ; DRIVER MUTATIONS ; GENOMIC COMPLEXITY
    Abstract: Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.
    Type of Publication: Journal article published
    PubMed ID: 24553142
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