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  • 1
    In: International Journal of Cancer, 01 January 2014, Vol.134(1), pp.21-31
    Description: The canonical Sonic Hedgehog (Shh)/Gli pathway plays multiples roles during central nervous system (CNS) development. To elucidate the molecular repertoire of Shh mediators, we have recently described novel transcriptional targets in response to Shh pathway modulation. Among them, we were able to identify Neogenin1 (Neo1), a death dependence receptor, as a new direct Shh downstream regulator in neural precursor proliferation. As appropriate Shh signaling is required for cerebellar growth and alterations cause Shh‐driven medulloblastoma (MB), here we have addressed the role of the Shh/Neogenin1 interaction in the context of cerebellar development and cancer. We demonstrate that the Shh pathway regulates Neogenin1 expression in mouse models that recapitulate the Shh MB subtype. We show that the canonical Shh pathway directly regulates the gene acting through an upstream sequence in its promoter both and in granule neuron precursor cells. We also identified and characterized a functional Gli‐binding site in the first intron of the human gene. Gene expression profiling of more than 300 MB shows that is indeed upregulated in SHH tumors compared to the other MB subgroups. Finally, we provide evidence that NEO1 is necessary for cell cycle progression in a human MB cell line, because a loss of function of arrests cells in the G2/M phase. Taken together, these results highlight Neogenin1 as a novel downstream effector of the Shh pathway in MB and a possible therapeutic target. What's new? Abnormal activation of the canonical Sonic Hedgehog (Shh)/Gli pathway has been associated with up to 30% of the human cases of medulloblastoma, which represents the most common malignant primary brain tumor in children. A greater knowledge of the cellular response to Shh pathway activation in the cerebellum is critical for both understanding disease formation and developing new treatments. In this study, the authors identified Neogenin‐1 as a novel downstream effector of the Shh pathway that mediates proliferation in both cultured cerebellar progenitors and shh‐driven medulloblastoma. The data suggest that targeting Neogenin‐1 could offer a promising alternative to current anti‐medulloblastoma therapies.
    Keywords: Medulloblastoma ; Sonic Hedgehog ; Neogenin 1 ; Gli ; Cancer
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 2
    Language: English
    In: International Journal of Cancer, 01 November 2011, Vol.129(9), pp.2297-2303
    Description: Pilocytic astrocytoma (PA) is emerging as a tumor entity with dysregulated Ras/Raf/MEK/ERK signaling. Common genetic lesions observed in PA, which are linked to aberrant ERK pathway activity, include either inactivation, or gain‐of‐function mutations. To investigate the mutation spectrum within the proto‐oncogene encoding the Ser/Thr‐kinase B‐Raf in more detail, we analyzed 64 primary tumor samples from children with PA including two patients with neurofibromatosis type 1 (NF1). The well‐known mutation was found in 6/64 (9.38%) of our samples. For the first time, we report concomitant presence of a somatic mutation in an NF1 patient indicating that more than one Ras/ERK pathway component can be affected in PA. Furthermore, 2/64 (3.13%) of our samples carried a 3‐bp insertion in resulting in the duplication of threonine 599. This conserved residue is located within the activation segment and, if phosphorylated in a Ras‐dependent manner, plays a key role in Raf activation. Here, we demonstrate that this mutant (B‐Raf) and another B‐Raf mutant, which carries two additional threonine residues at this position, display an kinase activity and cellular MEK/ERK activation potential comparable to those of B‐Raf. Notably, replacement of threonines by valine residues had similar effects on B‐Raf activity, suggesting that the distortion of the peptide backbone by additional amino acids rather than the insertion of additional, potential phosphorylation sites destabilizes the inactive conformation of the kinase domain. We also demonstrate that B‐Raf and B‐Raf, but not B‐Raf, provoke drastic morphological alterations in human astrocytes.
    Keywords: Pilocytic Astrocytoma ; Neurofibromatosis Type 1 ; B‐Raf ; Insertion Mutagenesis ; Mapk Pathway
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 3
    In: STEM CELLS, January 2014, Vol.32(1), pp.244-257
    Description: Data from transgenic mouse models show that neuronal progenitor cells (NPCs) migrate toward experimental brain tumors and modulate the course of pathology. However, the pathways whereby NPCs are attracted to CNS neoplasms are not fully understood and it is unexplored if NPCs migrate toward brain tumors (high‐grade astrocytomas) in humans. We analyzed the tumor‐parenchyma interface of neurosurgical resections for the presence of (NPCs) and distinguished these physiological cells from the tumor mass. We observed that polysialic acid neural cell adhesion molecule‐positive NPCs accumulate at the border of high‐grade astrocytomas and display a marker profile consistent with immature migratory NPCs. Importantly, these high‐grade astrocytoma‐associated NPCs did not carry genetic aberrations that are indicative of the tumor. Additionally, we observed NPCs accumulating in CNS metastases. These metastatic tumors are distinguished from neural cells by defined sets of markers. Transplanting murine glioma cells embedded in a cell‐impermeable hollow fiber capsule into the brains of nestin‐gfp reporter mice showed that diffusible factors are sufficient to induce a neurogenic reaction. In vitro, vascular endothelial growth factor (VEGF) secreted from glioma cells increases the migratory and proliferative behavior of adult human brain‐derived neural stem and progenitor cells via stimulation of VEGF receptor‐2 (VEGFR‐2). In vivo, inhibiting VEGFR‐2 signaling with a function‐blocking antibody led to a reduction in NPC migration toward tumors. Overall, our data reveal a mechanism by which NPCs are attracted to CNS tumors and suggest that NPCs accumulate in human high‐grade astrocytomas. S C
    Keywords: Glioma ; Psa‐Ncam ; Neuronal Progenitor ; Beta Iii‐Tubulin Protein ; Human
    ISSN: 1066-5099
    E-ISSN: 1549-4918
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  • 4
    In: Pediatric Blood & Cancer, July 2014, Vol.61(7), pp.1190-1194
    Description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1002/pbc.25002/abstract Byline: Vijay Ramaswamy, Marc Remke, David Shih, Xin Wang, Paul A. Northcott, Claudia C. Faria, Charles Raybaud, Uri Tabori, Cynthia Hawkins, James Rutka, Michael D. Taylor, Eric Bouffet Background Children presenting with medulloblastoma have a wide range of initial presenting symptoms. However, the influence of underlying tumor biology on the initial presentation of medulloblastoma is currently unknown. In light of the recent discovery of distinct medulloblastoma subgroups, we sought to define the initial presentation of childhood medulloblastoma in a subgroup specific manner. Procedure We assembled a cohort of 126 medulloblastoma cases at the Hospital for Sick Children between 1994 and 2012 and determined subgroup affiliation using nanoString. Clinical details pertaining to the initial presentation were determined through a retrospective chart review. Results The median pre-diagnostic interval across all medulloblastoma cases was 4 weeks (IQR: 4-12 weeks). Strikingly, when the pre-diagnostic interval was then determined in a subgroup specific manner, cases with WNT and Group 4 tumors showed significantly longer median pre-diagnostic intervals of 8 weeks compared to 2 weeks for SHH and 4 weeks for Group 3 (P=0.0001). Younger age was significantly associated with a prolonged pre-diagnostic interval (P=0.02 for all). When stratifying by subgroup the association with age was only significant in Group 4 (P=0.04 for Group 4). Improved survival was significantly associated with a longer pre-diagnostic interval (P=0.02), however is no longer significant when controlling for subgroup (P=0.07). Conclusions The duration of the pre-diagnostic interval in childhood medulloblastoma is highly subgroup dependent, further highlighting the clinical heterogeneity and biological relevance of the four principle subgroups of medulloblastoma. Pediatr Blood Cancer 2014;61:1190-1194. [c] 2014 Wiley Periodicals, Inc. Article Note: Conflict of interest: Nothing to declare. Supporting information: Additional Supporting Information may be found in the online version of this article Additional supporting information may be found in the online version of this article at the publisher's web-site. CAPTION(S): Fig. S1. Pre-diagnostic interval for the onset of symptoms as a function of percentage of patients diagnosed. A: Pre-diagnostic interval in weeks plotted as a function of the percentage of patients at initial diagnosis for all medulloblastoma's (n=126). B: Subgroup specific pre-diagnostic interval in weeks plotted as a function of the percentage of patients at initial diagnosis by subgroup. WNT (n=16), SHH (n=31), Group 3 (n=27), Group 4 (n=52), P=0.0001 (Kruskal-Wallis test). Fig. S2. A: Linear regression of the pre-diagnostic interval as a function of age at diagnosis. The solid line represents the best-fit regression line and dashed lines represent 95% confidence intervals. B: Subgroup specific linear regression of the pre-diagnostic interval as a function of age at diagnosis. Significant P-values 〈0.05 in bold. Fig. S3. Subgroup specific survival analysis. Survival stratified by median pre-diagnostic interval within each subgroup for (A) SHH, (B) Group 3, and (C) Group 4. Survival stratified by a pre-diagnostic interval above and below 12 weeks for (D) WNT, (E) Group 3, and (F) Group 4. No SHH cases had a pre-diagnostic c interval above 12 weeks. Table SI. Median Duration of Symptoms by Subgroup Divided by Weeks Table SII. Frequency of Presenting Symptoms by Subgroup in Children 〈3
    Keywords: Genomics ; Medulloblastoma ; Pediatric Brain Tumor ; Pre‐Diagnostic Interval ; Subgroups
    ISSN: 1545-5009
    E-ISSN: 1545-5017
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  • 5
    In: International Journal of Cancer, 15 December 2019, Vol.145(12), pp.3402-3413
    Description: Medulloblastoma is the most common malignant brain cancer in children. Since previous studies have mainly focused on alterations in the coding genome, our understanding of the contribution of long noncoding RNAs (lncRNAs) to medulloblastoma biology is just emerging. Using patient‐derived data, we show that the promoter of lncRNA is hypomethylated and that the transcript is highly expressed in the SHH subgroup. Furthermore, high expression of is correlated with poor outcome in patients with TP53 wild‐type SHH tumors. Silencing in medulloblastoma tumor cells induced apoptosis, while proliferation and migration were inhibited in culture. , silencing in medulloblastoma tumor cells resulted in reduced tumor growth, reduced proliferation of tumor cells, increased apoptosis and led to prolonged survival of tumor‐bearing mice. Together, our study suggests that the lncRNA is a prognostic marker and therapeutic target in medulloblastoma tumors and serves as a proof of concept that lncRNAs are important factors in the disease. What's new? Long non‐coding RNAs (lncRNAs) influence diverse cellular activities, including gene expression and the activity of adjacent genes. Hence, some lncRNAs are implicated in cancer. Here, the lncRNA was investigated for a possible functional role in medulloblastoma. was found to be overexpressed in medulloblastoma cells, with expression levels correlated to hypomethylation. Functionally, prevented cell death and promoted proliferation and tumorigenicity of medulloblastoma tumor cells and . Mice injected with knockdown medulloblastoma tumor cells exhibited reduced tumor growth and improved survival. The findings identify as a potential marker and therapeutic target in medulloblastoma.
    Keywords: Gene Regulation ; Sonic Hedgehog ; Oncogene
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 6
    In: Pediatric Blood & Cancer, June 2019, Vol.66(6), pp.n/a-n/a
    Description: Most medulloblastoma protocols worldwide include vincristine during radiation and chemotherapy. A significant dose‐limiting toxicity is peripheral neuropathy; however, there is a paucity of data to support the view that omission of vincristine does not impact survival. Herein we report two adolescent patients with Group 4 and SHH medulloblastoma, where vinblastine successfully replaced vincristine with resolution of their peripheral neuropathy. We furthermore show vinblastine is highly active in vitro and demonstrates equivalent antitumoral activity compared to vincristine. Substitution of vincristine with vinblastine in future studies should be considered for all patients with medulloblastoma, particularly those with hereditary neuropathy, severe vincristine toxicity, and adults.
    Keywords: Medulloblastoma ; Neuropathy ; Subgroup ; Vinblastine
    ISSN: 1545-5009
    E-ISSN: 1545-5017
    Source: John Wiley & Sons, Inc.
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  • 7
    Language: English
    In: Genes, Chromosomes and Cancer, July 2009, Vol.48(7), pp.558-568
    Description: Li–Fraumeni syndrome (LFS) represents an inherited tumor syndrome that is typically caused by germline mutations of the tumor suppressor gene . TP53 dysfunction secondarily disturbs the genetic integrity of the cell. Here, we report a family with LFS harboring a germline mutation (R248W) located in the functional domain of the protein that binds to the minor groove of the DNA. In this family, tumors of the central nervous system were diagnosed as primary malignancies in all carriers of the mutation. The index patient developed an anaplastic medulloblastoma with unusual genomic profile exhibiting six distinct high‐level genomic amplifications, two of them targeting the and genes, respectively. In an extrarenal rhabdoid tumor from the same patient, we found a novel high‐level amplification of the oncogene. The father of this patient was diagnosed with myxopapillary ependymoma (WHO °I), whereas a brother died from an early relapse of a choroid plexus carcinoma. The analysis of this LFS familiy thus revealed novel oncogene amplifications as different second hits that are likely to also play a role in the pathogenesis of their sporadic counterparts. © 2009 Wiley‐Liss, Inc.
    Keywords: Gene Amplification ; Germ-Line Mutation ; Li-Fraumeni Syndrome -- Genetics ; Tumor Suppressor Protein P53 -- Genetics;
    ISSN: 1045-2257
    E-ISSN: 1098-2264
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  • 8
    Language: English
    In: Genes, Chromosomes and Cancer, September 2007, Vol.46(9), pp.839-851
    Description: Supratentorial primitive neuroectodermal tumors (stPNETs) and medulloblastomas have long been thought to arise from a common cell type in the subventricular germinal matrix. Because of the infrequent occurrence of stPNETs, little is known about their genetic background. Here, we performed a genome‐wide screening for DNA copy‐number aberrations in 10 supratentorial PNETs using array‐based comparative genomic hybridization (array‐CGH). Comparing our findings with data from a previous array‐CGH study on 47 medulloblastomas, we identified differences in the frequency of copy‐number losses at chromosome regions 1p12‐22.1 and 9p, and gains at 19p, all of them more frequently occurring in stPNETs. In contrast to previous reports, we detected chromosome 17 aberrations by array‐CGH in 2/10 stPNETs. To validate our findings obtained by array‐CGH, we analyzed the loci of interest by fluorescence in situ hybridization in an independent set of 11 stPNETs and found deletions of 9p21 in 5/11 tumors of the second set, three of them being homozygous. All 9p21 deletions were associated with loss of CDKN2A protein expression. Altogether, deletions were detected in 7/21 stPNETs including four homozygous deletions, whereas such deletions were only found in 4/112 medulloblastomas, all of these being heterozygous ( 〈 0.001). Gains of 19p (14% vs. 0% in medulloblastomas, = 0.02) were found to be significantly more frequent in stPNETs, whereas gains of 17q (14% vs. 45% in medulloblastomas, = 0.02) were confirmed to be more frequent in medulloblastomas. These data further support the hypothesis of two different tumor entities of embryonal neuroepithelial tumors with characteristic genetic aberrations. © 2007 Wiley‐Liss, Inc.
    Keywords: Chromosome Deletion ; Cerebellar Neoplasms -- Genetics ; Cyclin-Dependent Kinase Inhibitor P16 -- Genetics ; Medulloblastoma -- Genetics ; Neuroectodermal Tumors, Primitive -- Genetics ; Supratentorial Neoplasms -- Genetics;
    ISSN: 1045-2257
    E-ISSN: 1098-2264
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