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  • 1
    Keywords: RECEPTOR ; ANGIOGENESIS ; CELLS ; EXPRESSION ; INHIBITOR ; INVASION ; SURVIVAL ; tumor ; Germany ; KINASE ; THERAPY ; TYROSINE KINASE ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; TUMORS ; TIME ; ACTIVATION ; FAMILY ; BIOLOGY ; NERVOUS-SYSTEM ; PATTERNS ; gene expression ; microarrays ; resistance ; LINE ; SIGNALING PATHWAYS ; LIGANDS ; PHENOTYPE ; CHILDREN ; RECEPTORS ; MICROARRAY ANALYSIS ; expression profiling ; PROGNOSTIC FACTOR ; neuroblastoma ; GROWTH-FACTOR-II ; INHIBITORS ; ABSENCE ; SINGLE ; PROGRAM ; OLIGONUCLEOTIDE ; SOLID TUMORS ; regulation ; PROGNOSTIC-FACTOR ; GENE-REGULATION ; NEUROTROPHIC FACTOR ; TARGET GENE ; gene regulation ; TARGET GENES ; PROFILES ; EXPRESSION PATTERNS ; EXPRESSION PROFILES ; HIGH EXPRESSION ; CYTOTOXIC DRUGS ; FACTOR BINDING-PROTEINS ; Trk receptors
    Abstract: Expression of neurotrophin receptors of the tyrosine kinase receptor (Trk) family is an important prognostic factor in solid tumors including neuroblastoma. High expression of TrkA (NTRK1) is associated with a favorable biology and outcome of neuroblastoma, whereas TrkB (NTRK2) is expressed on aggressive neuroblastomas with unfavorable outcome. To gain new insights into the global gene expression program resulting in these divergent biological phenotypes, we stably expressed either TrkA or TrkB in the human SH-SY5Y neuroblastoma cell line. Gene expression profiles were obtained from parental cells and transfectants activated by their ligands in a time course over 24 h using oligonucleotide microarrays. Basal activation of Trk receptors in the absence of exogenous ligand was sufficient to induce broad and divergent genetic changes. Global gene regulation following external ligand stimulation was surprisingly similar in SY5Y-TrkA and SY5Y-TrkB cells except for the differential expression of distinct novel target genes. Consistent with their divergent biological phenotype, SY5Y-TrkA cells were characterized by upregulation of proapoptotic genes and angiogenesis inhibitors, whereas SY5Y-TrkB cells demonstrated upregulation of genes involved in invasion or therapy resistance. We suggest that the transcriptional program of neuroblastoma cells is modulated by Trk-receptor expression and basal activation rather than by ligand-induced activation. Fine-tuning of the malignant phenotype may be achieved by additional ligand stimulation with subsequent activation of a few specific genes
    Type of Publication: Journal article published
    PubMed ID: 15637590
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  • 2
    Keywords: CANCER ; CELLS ; EXPRESSION ; SURVIVAL ; Germany ; INFORMATION ; RISK ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; ACCURACY ; validation ; PATIENT ; MARKER ; prognosis ; microarrays ; DESIGN ; PCR ; bioinformatics ; PREDICTION ; RISK ASSESSMENT ; experimental design ; CHILDREN ; real-time PCR ; expression profiling ; HIGH-LEVEL ; MYCN ; neuroblastoma ; ONCOLOGY ; RE ; ARRAY ; REAL-TIME ; analysis ; methods ; PROFILES ; EXPRESSION PROFILES ; USA ; correlation ; cancer research ; MICROARRAY PLATFORMS ; PREDICT ; quantitative ; PLATFORM ; outcome ; CLASSIFIERS
    Abstract: Purpose: To assess the feasibility of predicting neuroblastoma outcome using highly parallel quantitative real-time PCR data. Experimental Design: We generated expression profiles of 63 neuroblastoma patients, 47 of which were analyzed by both Affymetrix U95A microarrays and highly parallel real-time PCR on microfluidic cards (MFC; Applied Biosystems). Top-ranked genes discriminating patients with event-free survival or relapse according to high-level analysis of Affymetrix chip data, as well as known neuroblastoma marker genes (MYCN and NTRK1/TrkA), were quantified simultaneously by real-time PCR. Analysis of PCR data was accomplished using high-level bioinformatics methods including prediction analysis of microarray, significance analysis of microarray, and Computerized Affected Sibling Pair Analyzer and Reporter. Results: Internal validation of the MFC method proved it highly reproducible. Correlation of MFC and chip expression data varied markedly for some genes. Outcome prediction using prediction analysis of microarray on real-time PCR data resulted in 80% accuracy, which is comparable to results obtained using the Affymetrix platform. Real-time PCR data were useful for risk assessment of relapsing neuroblastoma (P = 0.0006, log-rank test) when Computerized Affected Sibling Pair Analyzer and Reporter analysis was applied. Conclusions: These data suggest that multiplex real-time PCR might be a promising approach to reduce the complexity of information obtained from whole-genome array experiments. It could provide a more convenient and less expensive too[ for routine application in a clinical setting
    Type of Publication: Journal article published
    PubMed ID: 17332289
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  • 3
    Keywords: CANCER ; EXPRESSION ; GROWTH ; tumor ; CELL ; MODEL ; PATHWAY ; PATHWAYS ; COHORT ; DISEASE ; GENE ; GENE-EXPRESSION ; RNA ; DIFFERENTIATION ; TUMORS ; ACTIVATION ; BINDING ; BIOLOGY ; TARGET ; CHROMATIN ; gene expression ; PROMOTER ; genetics ; MODULATION ; C-MYC ; REPRESSION ; TRANSCRIPTIONAL REPRESSION ; MYCN ; neuroblastoma ; N-MYC ; signaling ; ONCOLOGY ; B-CELL LYMPHOMAS ; miRNA ; outcome ; MICRORNA ; CELL BIOLOGY ; Genetic ; COHORTS ; EXPRESSION SIGNATURES ; PATHWAY DEREGULATION
    Abstract: Increased activity of MYC protein-family members is a common feature in many cancers. Using neuroblastoma as a tumor model, we established a microRNA (miRNA) signature for activated MYCN/c-MYC signaling in two independent primary neuroblastoma tumor cohorts and provide evidence that c-MYC and MYCN have overlapping functions. On the basis of an integrated approach including miRNA and messenger RNA (mRNA) gene expression data we show that miRNA activation contributes to widespread mRNA repression, both in c-MYC- and MYCN-activated tumors. c-MYC/MYCN-induced miRNA activation was shown to be dependent on c-MYC/MYCN promoter binding as evidenced by chromatin immunoprecipitation. Finally, we show that pathways, repressed through c-MYC/MYCN miRNA activation, are highly correlated to tumor aggressiveness and are conserved across different tumor entities suggesting that c-MYC/MYCN activate a core set of miRNAs for cooperative repression of common transcriptional programs related to disease aggressiveness. Our results uncover a widespread correlation between miRNA activation and c-MYC/MYCN-mediated coding gene expression modulation and further substantiate the overlapping functions of c-MYC and MYCN in the process of tumorigenesis. Oncogene (2010) 29, 1394-1404; doi:10.1038/onc.2009.429; published online 30 November 2009
    Type of Publication: Journal article published
    PubMed ID: 19946337
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  • 4
    Keywords: CANCER ; EXPRESSION ; CLASSIFICATION ; QUANTIFICATION ; GENE ; GENE-EXPRESSION ; TUMORS ; PATTERNS ; PATHOGENESIS ; REVEALS ; PREDISPOSITION ; ANAPLASTIC LYMPHOMA KINASE ; ACTIVATING MUTATIONS
    Abstract: Purpose: Genomic alterations of the anaplastic lymphoma kinase (ALK) gene have been postulated to contribute to neuroblastoma pathogenesis. This study aimed to determine the interrelation of ALK mutations, ALK expression levels, and clinical phenotype in primary neuroblastoma. Experimental Design: The genomic ALK status and global gene expression patterns were examined in 263 primary neuroblastomas. Allele-specific ALK expression was determined by cDNA cloning and sequencing. Associations of genomic ALK alterations and ALK expression levels with clinical phenotypes and transcriptomic profiles were compared. Results: Nonsynonymous point mutations of ALK were detected in 21 of 263 neuroblastomas (8%). Tumors with ALK mutations exhibited about 2-fold elevated median ALK mRNA levels in comparison with tumors with wild-type (WT) ALK. Unexpectedly, the WT allele was preferentially expressed in 12 of 21 mutated tumors. Whereas survival of patients with ALK mutated tumors was significantly worse as compared with the entire cohort of WT ALK patients, it was similarly poor in patients with WT ALK tumors in which ALK expression was as high as in ALK mutated neuroblastomas. Global gene expression patterns of tumors with ALK mutations or with high-level WT ALK expression were highly similar, and suggested that ALK may be involved in cellular proliferation in primary neuroblastoma. Conclusions: Primary neuroblastomas with mutated ALK exhibit high ALK expression levels and strongly resemble neuroblastomas with elevated WT ALK expression levels in both their clinical and molecular phenotypes. These data suggest that high levels of mutated and WT ALK mediate similar molecular functions that may contribute to a malignant phenotype in primary neuroblastoma.
    Type of Publication: Journal article published
    PubMed ID: 21632861
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  • 5
    Keywords: APOPTOSIS ; PATHWAY ; GENES ; POOR-PROGNOSIS ; INCREASED EXPRESSION ; MICE LACKING ; high-throughput analysis ; ISLAND METHYLATOR PHENOTYPE ; D-DEPENDENT KINASES ; INK4 FAMILY
    Abstract: Uncontrolled cell cycle entry, resulting from deregulated CDK-RB1-E2F pathway activity, is a crucial determinant of neuroblastoma cell malignancy. Here we identify neuroblastoma-suppressive functions of the p19-INK4d CDK inhibitor and uncover mechanisms of its repression in high-risk neuroblastomas. Reduced p19-INK4d expression was associated with poor event-free and overall survival and neuroblastoma risk factors including amplified MYCN in a set of 478 primary neuroblastomas. High MYCN expression repressed p19-INK4d mRNA and protein levels in different neuroblastoma cell models with conditional MYCN expression. MassARRAY and 450K methylation analyses of 105 primary neuroblastomas uncovered a differentially methylated region within p19-INK4d. Hypermethylation of this region was associated with reduced p19-INK4d expression. In accordance, p19-INK4d expression was activated upon treatment with the demethylating agent, 2'-deoxy-5-azacytidine, in neuroblastoma cell lines. Ectopic p19-INK4d expression decreased viability, clonogenicity and the capacity for anchorage-independent growth of neuroblastoma cells, and shifted the cell cycle towards the G1/0 phase. p19-INK4d also induced neurite-like processes and markers of neuronal differentiation. Moreover, neuroblastoma cell differentiation, induced by all-trans retinoic acid or NGF-NTRK1-signaling, activated p19-/NK4dexpression. Our findings pinpoint p19-INK4d as a neuroblastoma suppressor and provide evidence for MYCN-mediated repression and for epigenetic silencing of p19-INK4d by DNA hypermethylation in high-risk neuroblastomas.
    Type of Publication: Journal article published
    PubMed ID: 25104850
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  • 6
    Keywords: APOPTOSIS ; CANCER ; SUSCEPTIBILITY ; PROGRESSION ; CELL-LINE ; p53 ; CASPASE-8 ; chemosensitivity ; GENOTYPE ; MDM2 SNP309
    Abstract: Background: Neuroblastoma is a pediatric cancer that exhibits a wide clinical spectrum ranging from spontaneous regression in low-risk patients to fatal disease in high-risk patients. The identification of single nucleotide polymorphisms (SNPs) may help explain the heterogeneity of neuroblastoma and assist in identifying patients at higher risk for poor survival. SNPs in the TP53 pathway are of special importance, as several studies have reported associations between TP53 pathway SNPs and cancer. Of note, less than 2% of neuroblastoma tumors have a TP53 mutation at diagnosis. Patients and Methods: We selected 21 of the most frequently studied SNPs in the TP53 pathway and evaluated their association with outcome in 500 neuroblastoma patients using TaqMan allelic discrimination assays. Results and Conclusion: We investigated the impact of 21 SNPs on overall survival, event-free survival, age at diagnosis, MYCN status, and stage of the disease in 500 neuroblastoma patients. A missense SNP in exon 10 of the CASP8 gene SNP D302H was associated with worse overall and event-free survival in patients with MYCN-amplified neuroblastoma tumors.
    Type of Publication: Journal article published
    PubMed ID: 25502557
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  • 7
    Keywords: CANCER ; EXPRESSION ; SURVIVAL ; tumor ; Germany ; ALGORITHM ; CLASSIFICATION ; DIAGNOSIS ; DISEASE ; RISK ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; ACCURACY ; PATIENT ; ASSOCIATION ; NERVOUS-SYSTEM ; IDENTIFICATION ; PROGRESSION ; AMPLIFICATION ; PATTERNS ; gene expression ; microarrays ; VECTOR ; AGE ; chemotherapy ; RECURRENCE ; PROGNOSTIC-FACTORS ; PROGNOSTIC FACTORS ; SPONTANEOUS REGRESSION ; PREDICTION ; RISK ASSESSMENT ; sensitivity ; expression profiling ; PROGNOSTIC FACTOR ; neuroblastoma ; N-MYC ; CHILDHOOD ; PROGNOSTIC-FACTOR ; MYCN-AMPLIFICATION ; EXPRESSION PATTERNS ; SIGNATURE ; DISEASE PROGRESSION ; HIGH EXPRESSION ; outcome prediction
    Abstract: Neuroblastoma is a common childhood tumor comprising cases with rapid disease progression as well as spontaneous regression. Although numerous prognostic factors have been identified, risk evaluation in individual patients remains difficult. To de. ne a reliable prognostic predictor and gene signatures characteristic of biological subgroups, we performed mRNA expression profiling of 68 neuroblastomas of all stages. Expression data were analysed using support vector machines (SVM-rbf), prediction analysis of microarrays (PAM), k-nearest neighbors (k-NN) algorithms and multiple decision trees. SVM-rbf performed best of all methods, and predicted recurrence of neuroblastoma with an accuracy of 85% (sensitivity 77%, specificity 94%). PAM identified a classifer of 39 genes reliably predicting outcome with an accuracy of 80%. In comparison, conventional risk strati. cation based on stage, age and MYCN-status only reached a predictive accuracy of 64%. Kaplan-Meier analysis using the PAM classifer indicated a 5-year survival of 20 versus 78% for patients with unfavorably versus favorably predicted neuroblastomas, respectively (P=0.0001). Significance analysis of microarrays (SAM) identified additional genes differentially expressed among subgroups. MYCN-amplification and high expression of NTRK1/TrkA demonstrated a strong association with specific gene expression patterns. Our data suggest that microarray-derived data in addition to traditional clinical factors will be useful for risk assessment and de. ning biological properties of neuroblastoma
    Type of Publication: Journal article published
    PubMed ID: 16103881
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  • 8
    Keywords: CANCER ; CELLS ; EXPRESSION ; proliferation ; tumor ; TUMOR-CELLS ; CELL ; Germany ; PROTEIN ; transcription ; DIFFERENTIATION ; TUMORS ; LINES ; TRANSCRIPTION FACTOR ; MARKER ; primary ; CELL-LINES ; BREAST-CANCER ; CELL-LINE ; LINE ; PHENOTYPE ; PROGENITOR CELLS ; CHILDREN ; protein expression ; FACTOR AP-2 ; neuroblastoma ; ONCOLOGY ; CHILDHOOD ; INCREASE ; progenitor ; neural crest ; NOV ; SIRNA ; AP2alpha ; FACTOR AP-2-GAMMA ; Ganglioneuroma ; IHC ; TFAP2A
    Abstract: Neuroblastoma, the most common extracranial solid tumour of childhood, is derived from neural crest progenitor cells. The TFAP2a transcription factor regulates neural crest patterning. We analysed TFAP2a protein expression in 97 primary neuroblastic tumors and report that TFAP2a was strongly expressed in poorly differentiated neuroblastomas. TFAP2a expression in tumor cells of differentiated neuroblastic tumors was below detection. TFAP2a was strongly expressed in 4 of 6 neuroblastoma cell lines tested, and TFAP2a siRNA mediated knock down in SH-EP cells reduced proliferation and induced a more differentiated phenotype associated with an increase in the expression of the differentiation marker neurotensin. (C) 2008 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 18620802
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  • 9
    Keywords: CANCER ; EXPRESSION ; SURVIVAL ; CLASSIFICATION ; DIAGNOSIS ; INFORMATION ; SYSTEM ; COHORT ; DISEASE ; RISK ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; validation ; PATIENT ; prognosis ; SEQUENCE ; SEQUENCES ; IDENTIFICATION ; AMPLIFICATION ; gene expression ; MICROARRAY DATA ; microarrays ; DESIGN ; NUMBER ; CANCER-PATIENTS ; PREDICTION ; SELECTION ; CANCER PATIENTS ; neuroblastoma ; ONCOLOGY ; GENE-EXPRESSION PROFILES ; development ; prospective ; RISK STRATIFICATION ; outcome ; SIGNATURES ; EXPRESSION SIGNATURES ; STRATIFICATION
    Abstract: Purpose: Reliable prognostic stratification remains a challenge for cancer patients, especially for diseases with variable clinical course such as neuroblastoma. Although numerous studies have shown that outcome might be predicted using gene expression signatures, independent cross-platform validation is often lacking. Experimental Design: Using eight independent studies comprising 933 neuroblastoma patients, a prognostic gene expression classifier was developed, trained, tested, and validated. The classifier was established based on reanalysis of four published studies with updated clinical information, reannotation of the probe sequences, common risk definition for training cases, and a single method for gene selection (prediction analysis of microarray) and classification (correlation analysis). Results: Based on 250 training samples from four published microarray data sets, a correlation signature was built using 42 robust prognostic genes. The resulting classifier was validated on 351 patients from four independent and unpublished data sets and on 129 remaining test samples from the published studies. Patients with divergent outcome in the total cohort, as well as in the different risk groups, were accurately classified (log-rank P 〈 0.001 for overall and progression-free survival in the four independent data sets). Moreover, the 42-gene classifier was shown to be an independent predictor for survival (odds ratio, 〉5). Conclusion: The strength of this 42-gene classifier is its small number of genes and its cross-platform validity in which it outperforms other published prognostic signatures. The robustness and accuracy of the classifier enables prospective assessment of neuroblastoma patient outcome. Most importantly, this gene selection procedure might be an example for development and validation of robust gene expression signatures in other cancer entities. Clin Cancer Res; 16(5); 1532-41. (C)2010 AACR
    Type of Publication: Journal article published
    PubMed ID: 20179214
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  • 10
    Keywords: PROTEIN ; LINES ; Germany ; CELL ; MYCN ; neuroblastoma ; CELL-LINES ; TARGET ; REPAIR ; CELL-LINE ; resistance ; LINE
    Type of Publication: Meeting abstract published
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