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  • Jabado, Nada  (30)
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  • 1
    In: Neuro-Oncology, 2015, Vol. 17(suppl3), pp.iii24-iii24
    Description: Genome-wide profiling and next-generation based sequencing studies have dramatically improved our understanding of embryonal brain tumor (EBT) biology in the recent years. However, the vast majority of these studies are based on the assumption that single biopsies are representative for the entire primary tumor. Intratumor heterogeneity constitutes a common phenomenon previously described in renal cell carcinoma (RCC) and high-grade glioma (HGG). Highly disparate molecular profiles of spatially separated tumor areas within the same tumor may preclude development of molecularly targeted therapies based on single tumor biopsies.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    Language: English
    In: Cancer Research, 04/15/2013, Vol.73(8 Supplement), pp.3552-3552
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 3
  • 4
    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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  • 5
    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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  • 6
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 15 August 2015, Vol.21(16), pp.3750-8
    Description: Myxopapillary ependymoma (MPE) is a distinct histologic variant of ependymoma arising commonly in the spinal cord. Despite an overall favorable prognosis, distant metastases, subarachnoid dissemination, and late recurrences have been reported. Currently, the only effective treatment for MPE is gross-total resection. We characterized the genomic and transcriptional landscape of spinal ependymomas in an effort to delineate the genetic basis of this disease and identify new leads for therapy. Gene expression profiling was performed on 35 spinal ependymomas, and copy number profiling was done on an overlapping cohort of 46 spinal ependymomas. Functional validation experiments were performed on tumor lysates consisting of assays measuring pyruvate kinase M activity (PKM), hexokinase activity (HK), and lactate production. At a gene expression level, we demonstrate that spinal grade II and MPE are molecularly and biologically distinct. These are supported by specific copy number alterations occurring in each histologic variant. Pathway analysis revealed that MPE are characterized by increased cellular metabolism, associated with upregulation of HIF1α. These findings were validated by Western blot analysis demonstrating increased protein expression of HIF1α, HK2, PDK1, and phosphorylation of PDHE1A. Functional assays were performed on MPE lysates, which demonstrated decreased PKM activity, increased HK activity, and elevated lactate production. Our findings suggest that MPE may be driven by a Warburg metabolic phenotype. The key enzymes promoting the Warburg phenotype: HK2, PKM2, and PDK are targetable by small-molecule inhibitors/activators, and should be considered for evaluation in future clinical trials for MPE.
    Keywords: DNA Copy Number Variations -- Genetics ; Ependymoma -- Genetics ; Spinal Neoplasms -- Genetics ; Transcriptome -- Genetics
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 7
    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-[beta] signalling in Group 3, and NF-[kappa]B signalling in Group 4, suggest future avenues for rational, targeted therapy.
    Keywords: Medulloblastoma – Physiological Aspects ; Medulloblastoma – Genetic Aspects ; Genetic Variation – Research ; Cancer Genetics – Research ; Cancer Metastasis – Research;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 8
    In: Neuro-Oncology, 2014, Vol. 16(suppl5), pp.v102-v102
    Description: INTRODUCTION: Comprehensive, genome-wide profiling and next-generation sequencing based studies have dramatically improved our understanding of pediatric brain tumor biology in recent years. However, the vast majority of these studies rely on the assumption that single biopsies are representative of all areas within a tumor. Intratumor heterogeneity comprises a common phenomenon previously described in glioblastoma multiforme and other tumors. Highly disparate genetic profiles of spatially separated areas within the same tumor may preclude development of personalized, molecularly targeted therapies based on single tumor biopsies. MATERIAL AND METHODS: To assess the degree of intratumor heterogeneity, we conducted multiregion whole exome sequencing, high-resolution DNA copy number analysis (Cytoscan HD) and DNA methylation profiling (Infinium HumanMethylation450 BeadChip) on over 25 distinct pediatric and adult brain tumors with a median of six biopsies per tumor (range 4-9). Histological entities comprised ATRT (n = 2), DIPG (n = 2), ependymoma (n = 1), glioblastoma (n = 10), medulloblastoma (n = 10), and medulloepithelioma (n = 1). We elucidated the degree of intratumor heterogeneity and subgroup affiliation using integrated genomics and unsupervised hierarchical clustering algorithms. RESULTS: Epigenetic signatures were highly similar in multiregion biopsies from a single tumor. However, we identified up to 250,000 CpG dinucleotides that were differentially methylated when determining the intertumor heterogeneity of DNA methylation patterns even within disease subgroups. In addition, pediatric brain tumors displayed highly similar focal and broad DNA copy number alterations compared to their adult counterparts. Multiregion sequencing further reinforced the relatively higher degree of intratumor homogeneity in pediatric brain tumors. Lastly, we showed that subgroup affiliation was stable in all multiregion biopsies in medulloblastomas and glioblastomas. CONCLUSIONS: Our results reveal that single biopsies are representative of the tumor genomics landscape in pediatric brain tumors and that DNA methylation based subgrouping is geographically stable.
    Keywords: Glioblastoma ; Pediatrics ; Glioblastoma Multiforme ; Landscape ; Algorithms ; Oncology ; Biopsy ; Cpg Islands ; Copy Number ; Brain Tumors ; DNA Sequencing ; Epigenetics ; DNA Methylation ; Medulloblastoma ; Genomics ; Neurology & Neuropathology;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 9
    Language: English
    In: Cell, 20 January 2012, Vol.148(1-2), pp.59-71
    Description: Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer. ► Complex chromosomal alterations (chromothripsis) observed in medulloblastomas ► Cancers with such alterations harbor TP53 mutations ► Context-specific link between the status of p53 and likelihood of chromothripsis ► p53 status and chromothripsis also correlate with aggressive acute myeloid leukemia Connecting p53 status and chromothripsis in specific types of cancer provides a genetic basis for the more aggressive forms of medulloblastoma and leukemia.
    Keywords: Biology
    ISSN: 0092-8674
    E-ISSN: 1097-4172
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  • 10
    In: Nature, 2016, Vol.529(7586), p.351
    Description: The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (〈5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (〈12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.
    Keywords: Medulloblastoma – Genetic Aspects ; Medulloblastoma – Care and Treatment ; Clonal Selection (Immunology) – Research;
    ISSN: 0028-0836
    E-ISSN: 14764687
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