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  • 1
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    Identification of ALK as a major familial neuroblastoma predisposition gene (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-08-30
    Description: Neuroblastoma is a childhood cancer that can be inherited, but the genetic aetiology is largely unknown. Here we show that germline mutations in the anaplastic lymphoma kinase (ALK) gene explain most hereditary neuroblastomas, and that activating mutations can also be somatically acquired. We first identified a significant linkage signal at chromosome bands 2p23-24 using a whole-genome scan in neuroblastoma pedigrees. Resequencing of regional candidate genes identified three separate germline missense mutations in the tyrosine kinase domain of ALK that segregated with the disease in eight separate families. Resequencing in 194 high-risk neuroblastoma samples showed somatically acquired mutations in the tyrosine kinase domain in 12.4% of samples. Nine of the ten mutations map to critical regions of the kinase domain and were predicted, with high probability, to be oncogenic drivers. Mutations resulted in constitutive phosphorylation, and targeted knockdown of ALK messenger RNA resulted in profound inhibition of growth in all cell lines harbouring mutant or amplified ALK, as well as in two out of six wild-type cell lines for ALK. Our results demonstrate that heritable mutations of ALK are the main cause of familial neuroblastoma, and that germline or acquired activation of this cell-surface kinase is a tractable therapeutic target for this lethal paediatric malignancy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2672043/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2672043/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mosse, Yael P -- Laudenslager, Marci -- Longo, Luca -- Cole, Kristina A -- Wood, Andrew -- Attiyeh, Edward F -- Laquaglia, Michael J -- Sennett, Rachel -- Lynch, Jill E -- Perri, Patrizia -- Laureys, Genevieve -- Speleman, Frank -- Kim, Cecilia -- Hou, Cuiping -- Hakonarson, Hakon -- Torkamani, Ali -- Schork, Nicholas J -- Brodeur, Garrett M -- Tonini, Gian P -- Rappaport, Eric -- Devoto, Marcella -- Maris, John M -- K08 CA111733/CA/NCI NIH HHS/ -- K08 CA111733-04/CA/NCI NIH HHS/ -- K08-111733/PHS HHS/ -- R01 CA078545/CA/NCI NIH HHS/ -- R01 CA078545-09/CA/NCI NIH HHS/ -- R01 CA124709/CA/NCI NIH HHS/ -- R01-CA78454/CA/NCI NIH HHS/ -- R01-CA87847/CA/NCI NIH HHS/ -- U10 CA098543/CA/NCI NIH HHS/ -- U10 CA098543-06/CA/NCI NIH HHS/ -- England -- Nature. 2008 Oct 16;455(7215):930-5. doi: 10.1038/nature07261. Epub 2008 Aug 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18724359" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Cell Line, Tumor ; Child ; Chromosomes, Human, Pair 2/genetics ; Female ; Gene Dosage ; Gene Expression Regulation, Neoplastic ; Genetic Predisposition to Disease/*genetics ; Germ-Line Mutation/genetics ; Humans ; Male ; Models, Molecular ; Molecular Sequence Data ; Mutation/*genetics ; Neuroblastoma/*enzymology/*genetics ; Pedigree ; Phosphorylation ; Protein Structure, Tertiary ; Protein-Tyrosine Kinases/chemistry/deficiency/*genetics ; Receptor Protein-Tyrosine Kinases
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Copy number variation at 1q21.1 associated with neuroblastoma (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-06-19
    Description: Common copy number variations (CNVs) represent a significant source of genetic diversity, yet their influence on phenotypic variability, including disease susceptibility, remains poorly understood. To address this problem in human cancer, we performed a genome-wide association study of CNVs in the childhood cancer neuroblastoma, a disease in which single nucleotide polymorphism variations are known to influence susceptibility. We first genotyped 846 Caucasian neuroblastoma patients and 803 healthy Caucasian controls at approximately 550,000 single nucleotide polymorphisms, and performed a CNV-based test for association. We then replicated significant observations in two independent sample sets comprised of a total of 595 cases and 3,357 controls. Here we describe the identification of a common CNV at chromosome 1q21.1 associated with neuroblastoma in the discovery set, which was confirmed in both replication sets. This CNV was validated by quantitative polymerase chain reaction, fluorescent in situ hybridization and analysis of matched tumour specimens, and was shown to be heritable in an independent set of 713 cancer-free parent-offspring trios. We identified a previously unknown transcript within the CNV that showed high sequence similarity to several neuroblastoma breakpoint family (NBPF) genes and represents a new member of this gene family (NBPF23). This transcript was preferentially expressed in fetal brain and fetal sympathetic nervous tissues, and the expression level was strictly correlated with CNV state in neuroblastoma cells. These data demonstrate that inherited copy number variation at 1q21.1 is associated with neuroblastoma and implicate a previously unknown neuroblastoma breakpoint family gene in early tumorigenesis of this childhood cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755253/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755253/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Diskin, Sharon J -- Hou, Cuiping -- Glessner, Joseph T -- Attiyeh, Edward F -- Laudenslager, Marci -- Bosse, Kristopher -- Cole, Kristina -- Mosse, Yael P -- Wood, Andrew -- Lynch, Jill E -- Pecor, Katlyn -- Diamond, Maura -- Winter, Cynthia -- Wang, Kai -- Kim, Cecilia -- Geiger, Elizabeth A -- McGrady, Patrick W -- Blakemore, Alexandra I F -- London, Wendy B -- Shaikh, Tamim H -- Bradfield, Jonathan -- Grant, Struan F A -- Li, Hongzhe -- Devoto, Marcella -- Rappaport, Eric R -- Hakonarson, Hakon -- Maris, John M -- GM081519/GM/NIGMS NIH HHS/ -- R00 CA151869/CA/NCI NIH HHS/ -- R01 CA087847/CA/NCI NIH HHS/ -- R01 CA087847-05/CA/NCI NIH HHS/ -- R01 CA124709/CA/NCI NIH HHS/ -- R01 CA124709-02/CA/NCI NIH HHS/ -- R01-CA124709/CA/NCI NIH HHS/ -- R01-CA87847/CA/NCI NIH HHS/ -- T32-HG000046/HG/NHGRI NIH HHS/ -- U10 CA098543/CA/NCI NIH HHS/ -- U10 CA098543-07/CA/NCI NIH HHS/ -- U10-CA98543/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Jun 18;459(7249):987-91. doi: 10.1038/nature08035.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19536264" target="_blank"〉PubMed〈/a〉
    Keywords: Child ; Chromosome Breakage ; Chromosomes, Human, Pair 1/*genetics ; European Continental Ancestry Group/genetics ; Fetus/metabolism ; Gene Dosage/*genetics ; Genetic Predisposition to Disease/genetics ; Genetic Variation/*genetics ; Genome-Wide Association Study ; Genotype ; Humans ; In Situ Hybridization, Fluorescence ; Neuroblastoma/*genetics ; Polymerase Chain Reaction ; Polymorphism, Single Nucleotide/genetics ; RNA, Messenger/genetics ; Reproducibility of Results
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Integrative genomics identifies LMO1 as a neuroblastoma oncogene (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-12-03
    Description: Neuroblastoma is a childhood cancer of the sympathetic nervous system that accounts for approximately 10% of all paediatric oncology deaths. To identify genetic risk factors for neuroblastoma, we performed a genome-wide association study (GWAS) on 2,251 patients and 6,097 control subjects of European ancestry from four case series. Here we report a significant association within LIM domain only 1 (LMO1) at 11p15.4 (rs110419, combined P = 5.2 x 10(-16), odds ratio of risk allele = 1.34 (95% confidence interval 1.25-1.44)). The signal was enriched in the subset of patients with the most aggressive form of the disease. LMO1 encodes a cysteine-rich transcriptional regulator, and its paralogues (LMO2, LMO3 and LMO4) have each been previously implicated in cancer. In parallel, we analysed genome-wide DNA copy number alterations in 701 primary tumours. We found that the LMO1 locus was aberrant in 12.4% through a duplication event, and that this event was associated with more advanced disease (P 〈 0.0001) and survival (P = 0.041). The germline single nucleotide polymorphism (SNP) risk alleles and somatic copy number gains were associated with increased LMO1 expression in neuroblastoma cell lines and primary tumours, consistent with a gain-of-function role in tumorigenesis. Short hairpin RNA (shRNA)-mediated depletion of LMO1 inhibited growth of neuroblastoma cells with high LMO1 expression, whereas forced expression of LMO1 in neuroblastoma cells with low LMO1 expression enhanced proliferation. These data show that common polymorphisms at the LMO1 locus are strongly associated with susceptibility to developing neuroblastoma, but also may influence the likelihood of further somatic alterations at this locus, leading to malignant progression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3320515/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3320515/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Kai -- Diskin, Sharon J -- Zhang, Haitao -- Attiyeh, Edward F -- Winter, Cynthia -- Hou, Cuiping -- Schnepp, Robert W -- Diamond, Maura -- Bosse, Kristopher -- Mayes, Patrick A -- Glessner, Joseph -- Kim, Cecilia -- Frackelton, Edward -- Garris, Maria -- Wang, Qun -- Glaberson, Wendy -- Chiavacci, Rosetta -- Nguyen, Le -- Jagannathan, Jayanti -- Saeki, Norihisa -- Sasaki, Hiroki -- Grant, Struan F A -- Iolascon, Achille -- Mosse, Yael P -- Cole, Kristina A -- Li, Hongzhe -- Devoto, Marcella -- McGrady, Patrick W -- London, Wendy B -- Capasso, Mario -- Rahman, Nazneen -- Hakonarson, Hakon -- Maris, John M -- 9024/Cancer Research UK/United Kingdom -- R00 CA151869/CA/NCI NIH HHS/ -- R01 CA124709/CA/NCI NIH HHS/ -- R01 CA124709-05/CA/NCI NIH HHS/ -- R01-CA124709/CA/NCI NIH HHS/ -- U10-CA98413/CA/NCI NIH HHS/ -- U10-CA98543/CA/NCI NIH HHS/ -- UL1-RR024134-03/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Jan 13;469(7329):216-20. doi: 10.1038/nature09609. Epub 2010 Dec 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21124317" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Cell Line, Tumor ; Cell Proliferation ; Chromosomes, Human, Pair 11/genetics ; DNA Copy Number Variations/genetics ; DNA-Binding Proteins/*genetics ; Disease Progression ; Europe/ethnology ; Gene Duplication/genetics ; Gene Expression Regulation, Neoplastic/genetics ; Genetic Predisposition to Disease/*genetics ; Genome, Human/genetics ; *Genome-Wide Association Study ; Genomics ; Genotype ; Humans ; LIM Domain Proteins ; Neuroblastoma/*genetics/pathology ; Odds Ratio ; Oncogenes/*genetics ; Phenotype ; Polymorphism, Single Nucleotide/genetics ; Survival Rate ; Transcription Factors/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    RNAi screen of the protein kinome identifies checkpoint kinase 1 (CHK1) as a therapeutic target in neuroblastoma (2011)
    National Academy of Sciences
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    Publication Date: 2011-02-02
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 5
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    RNAi screen of the protein kinome identifies checkpoint kinase 1 (CHK1) as a therapeutic target in neuroblastoma [Medical Sciences] (2011)
    National Academy of Sciences
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    Publication Date: 2011-02-23
    Description: Neuroblastoma is a childhood cancer that is often fatal despite intense multimodality therapy. In an effort to identify therapeutic targets for this disease, we performed a comprehensive loss-of-function screen of the protein kinome. Thirty kinases showed significant cellular cytotoxicity when depleted, with loss of the cell cycle checkpoint kinase 1 (CHK1/CHEK1) being the most potent. CHK1 mRNA expression was higher in MYC–Neuroblastoma-related (MYCN)–amplified (P 〈 0.0001) and high-risk (P = 0.03) tumors. Western blotting revealed that CHK1 was constitutively phosphorylated at the ataxia telangiectasia response kinase target site Ser345 and the autophosphorylation site Ser296 in neuroblastoma cell lines. This pattern was also seen in six of eight high-risk primary tumors but not in control nonneuroblastoma cell lines or in seven of eight low-risk primary tumors. Neuroblastoma cells were sensitive to the two CHK1 inhibitors SB21807 and TCS2312, with median IC50 values of 564 nM and 548 nM, respectively. In contrast, the control lines had high micromolar IC50 values, indicating a strong correlation between CHK1 phosphorylation and CHK1 inhibitor sensitivity (P = 0.0004). Furthermore, cell cycle analysis revealed that CHK1 inhibition in neuroblastoma cells caused apoptosis during S-phase, consistent with its role in replication fork progression. CHK1 inhibitor sensitivity correlated with total MYC(N) protein levels, and inducing MYCN in retinal pigmented epithelial cells resulted in CHK1 phosphorylation, which caused growth inhibition when inhibited. These data show the power of a functional RNAi screen to identify tractable therapeutical targets in neuroblastoma and support CHK1 inhibition strategies in this disease.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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