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  • 1
    Abstract: Ependymoma is a malignant pediatric brain tumor, often incurable under the current treatment regimen. We aimed to evaluate the expression of microRNAs (miRs) in pediatric ependymoma tumors in an attempt to identify prognostic molecular markers which would lead to potential therapeutic targets. Following miR-array expression analysis, we focused on 9 miRs that correlated with relapse which were further validated by quantitative real-time PCR (qRT-PCR) in a cohort of 67 patients. Western blotting and immunohistochemistry were used to measure target protein expression in 20 and 34 tumor samples, respectively. High expression of miR-124-3p significantly correlated with the lower progression-free survival (PFS) of 16% compared to 67% in those expressing low levels (P = .002). Interestingly, in the group of patients with local disease (n = 56) expression levels of this miR distinguished 2 subgroups with a significantly different outcome (P = .001). miR-124-3p was identified as an independent prognostic factor of relapse in the multivariate analysis performed in the whole cohort and in the group with localized disease. In the localized group, a patient expressing high levels of miR-124-3p had a 4.1-fold increased risk for relapse (P = .005). We demonstrated the direct binding of miR-124-3p to its target TP53INP1. Negative TP53INP1 protein levels correlated with a poor outcome (P = .034). We propose miR-124-3p and TP53INP1 as new biomarkers for prognostic stratification that may be possible therapeutic targets for ependymoma.
    Type of Publication: Journal article published
    PubMed ID: 28437838
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  • 2
    Keywords: Germany ; MODEL ; HYBRIDIZATION ; PATIENT ; prognosis ; chromosome ; DELETION ; IN-SITU ; COMPARATIVE GENOMIC HYBRIDIZATION ; NUMBER ; ABERRATIONS ; IN-SITU HYBRIDIZATION ; MUTATIONS ; PROBES ; EVOLUTION ; ABNORMALITIES ; FLUORESCENCE ; POOR-PROGNOSIS ; GLOBAL GENE-EXPRESSION ; MULTIPLE-MYELOMA ; CLUSTER ; CHROMOSOMES ; in situ hybridization ; multiple myeloma ; IV ; TREE MODELS ; cytogenetic ; cluster analysis ; EVENTS ; 11Q23 ; 14Q32 TRANSLOCATIONS ; 19Q ; CHROMOSOME-13 ; DOSE CHEMOTHERAPY ; HYPODIPLOIDY ; IgH rearrangement ; REARRANGEMENTS
    Abstract: To delineate multiple myeloma (MM) subgroups and their clonal evolution, we analyzed 81 newly diagnosed patients by interphase fluorescence in situ hybridization using a comprehensive probe set for 10 chromosomes and two IGH rearrangements. A median of 5 probes per patient displayed aberrant signal numbers (range, 1-10). Additional copies most frequently found were for 15q22, 19q13, 9q34, 11q23, and 1q21. Losses commonly observed were of 13q 14.3, 17p 13, and 22q 11. Predominance of gain or loss was quantified by a copy number score (CS) for each patient. Two peaks (CS = +3 and CS = 0) were found by plotting patient copy number scores over CS values corresponding to hyperdiploid and nonhyperdiploid MM. Cluster analysis revealed four major branches: (i) gain of 9q, 15q, 19q, and/or 11q; (ii) deletion of 13q and t(4; 14); (iii) t(11; 14); and (iv) gain of 1q. Statistical modeling of an oncogenetic tree indicated that early independent events were gain of 15q/9q and/or 11q, t(11; 14); deletion of 13q followed by t(4; 14); and gain of 1q. Aberrations of 17p13, 22q11, 8p12, and 6q21 were found as subsequent events. MM with gain of I q was delineated as a subentity with significantly higher beta-2-microglobulin and lower hemoglobin levels, indicating a poor prognosis. From our results, we propose a model of MM for clonal evolution. (c) 2005 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 16001433
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  • 3
    Keywords: CELLS ; EXPRESSION ; SURVIVAL ; Germany ; GENE ; GENE-EXPRESSION ; GENES ; PROTEIN ; transcription ; PATIENT ; MECHANISM ; FAMILY ; TRANSCRIPTION FACTOR ; chromosome ; DELETION ; LYMPHOMA ; gene expression ; DISRUPTION ; UP-REGULATION ; MUTATION ; leukemia ; DELETIONS ; inactivation ; TUMOR-SUPPRESSOR GENE ; REGION ; B-CELLS ; point mutation ; TRANSCRIPTS ; molecular ; TUMOR-SUPPRESSOR ; ACUTE MYELOID-LEUKEMIA ; regulation ; ATM MUTATIONS ; B-CLL ; tumor suppressor gene ; transcript ; 11Q23 ; ATM ; CYCLIN-E ; GENOMIC REGION ; GTPASE-ACTIVATING PROTEIN ; INDUCED SKIN TUMORS ; MLL
    Abstract: Deletion of chromosome region 11q22-q23 defines a subgroup of patients with B-cell chronic lymphocytic leukemia (B-CLL) characterized by poor survival. Although the tumor-suppressor gene ATM in the consensus deletion region was found to be biallelically inactivated in about one third of B-CLL cases, in the majority of those who have this deletion, inactivation of the remaining ATM allele was not observed. To identify a second disease-associated gene, we investigated two B-CLL cases with translocation breakpoints in the critical 11q23 deletion region. In one case, a t(X;11)(q13;q23) was cloned and two novel genes were isolated. The breakpoint on 11q23 affected the ARHGAP20 gene, which encodes a protein predicted to be involved in the regulation of Rho family GTPases. The breakpoint on Xq13 occurred in BRWD3, which codes for a putative novel transcription factor. The rearrangement of ARHGAP20 and BRWD3 did not result in fusion transcripts, but it disrupted both genes. Mutation analysis of 28 B-CLL samples with monoallelic deletions and two B-CLL samples with 11q23 translocations detected no deleterious mutation in the remaining copy of ARHGAP20. Quantitative expression analysis in 22 B-CLLs revealed significant up-regulation of ARHGAP20 in CLL B cells, whereas BRWD3 was slightly down-regulated. Thus, deregulation of ARHGAP20 by altered gene expression or by gene disruption (but not point mutation) might be a general molecular mechanism of B-CLL leukemogenesis. (C) 2004 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 15543602
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  • 4
    Keywords: EXPRESSION ; tumor ; carcinoma ; Germany ; GENE ; GENES ; HYBRIDIZATION ; microarray ; PROTEIN ; TISSUE ; TUMORS ; DNA ; PROGRESSION ; AMPLIFICATION ; COMPARATIVE GENOMIC HYBRIDIZATION ; microarrays ; HEAD ; NECK ; squamous cell carcinoma ; PROGNOSTIC VALUE ; CYCLIN D1 OVEREXPRESSION ; OVEREXPRESSION ; POOR-PROGNOSIS ; CHROMOSOMAL IMBALANCES ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; CANDIDATE GENES ; tissue microarray analysis ; SPECIMENS ; ARRAY CGH
    Abstract: Chromosomal band 11q13 is frequently amplified in oral squamous cell carcinoma (OSCC) and assumed to be critically involved in tumor initiation and progression by proto-oncogene activation. Though cyclin D1 (CCND1) is supposed to be the most relevant oncogene, several additional putative candidate genes are inside this chromosomal region, for which their actual role in tumorigenesis still needs to be elucidated. To characterize the 11q13 amplicon in detail, 40 OSCCs were analyzed by comparative genomic hybridization to DNA microarrays (matrix-CGH) containing BAC clones derived from chromosomal band 11q13. This high-resolution approach revealed a consistent amplicon about 1.7 Mb in size including the CCND1 oncogene. Seven BAC clones covering FGF3, EMS1, and SHANK2 were shown to be frequently coamplified inside the CCND1 amplicon. Subsequent analysis of tissue microarrays; by FISH revealed amplification frequencies of 36.8% (88/239) for CCND1, 34.3% (60/ 175) for FGF3, 37.4% (68/182) for EMS1, and 36.3% (61/168) for SHANK2. Finally, quantitative mRNA expression analysis demonstrated consistent overexpression of CCND1 in all tumors and of EMS1 and SHANK2 in a subset of specimens with 11q13 amplification, but no expression of FGF3 in any of the cases. Our study underlines the critical role of CCND1 in OSCC development and additionally points to the functionally related genes EMS1 and SHANK2, both encoding for cytoskeleton-associated proteins, which are frequently coamplified with CCND1 and therefore could cooperatively contribute to OSCC pathogenesis. (c) 2005 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 16235239
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  • 5
    Keywords: ACTIVATION, CHILDHOOD MEDULLOBLASTOMA, CLUSTER, COMPARATIVE GENOMIC HYBRIDIZATION, COPY NUMBER, COPY
    Abstract: Medulloblastoma is a highly malignant embryonal tumor of the cerebellum that accounts for 20%-25% of all intracranial pediatric tumors. The most frequent chromosomal rearrangement in medulloblastoma is isochromosome 17, or i(17q). Its frequency suggests that it serves an important role in tumor pathogenesis, possibly mediated by the disruption or permanent activation of a gene at the breakpoint. To address this question, we performed a detailed analysis of chromosome 17 DNA copy number from 18 medulloblastomas previously shown to carry an apparent i(17q). We identified two breakpoint regions, one well within band 17p 11.2 (n = 16) and a second within the pericentromeric region (n = 2). To map the breakpoints more,precisely. we constructed a tiling-path matrix-CGH array covering chromosomal band 17p 11.2 to the centromere and utilized it to delineate two small breakpoint intervals mapping at Mb 19.0 and 21.7 in seven of the medulloblastomas and in nine hematological neoplasias with i(17q). The former interval contains two breakpoint clusters that each colocalize with a pair of head-tohead inverted DNA sequence repeats, and the latter maps close to a region of a-satellite repeats. No consensus coding sequence localizes in these regions. Together, these data strongly suggest that the effects of i(17q) in medulloblastorna are mediated by gene-dosage effects of genes on 17p or 17q rather than by the disruption or deregulation of a "breakpoint" gene. Furthermore, we identified artifacts introduced in DNA copy number data by cross-hybridization of low-copy repeat sequences and discuss the challenge these can pose in the interpretation of diagnostic microarrays. (c) 2006 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 16419060
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  • 6
    Keywords: tumor ; Germany ; COHORT ; GENE ; HYBRIDIZATION ; TUMORS ; PATIENT ; MARKER ; SEQUENCE ; DELETION ; STAGE ; AMPLIFICATION ; COMPARATIVE GENOMIC HYBRIDIZATION ; COPY NUMBER ; PATTERNS ; microarrays ; NUMBER ; MARKERS ; REGION ; REGIONS ; PHENOTYPE ; REVEALS ; CHILDREN ; SEGMENTS ; 1p ; neuroblastoma ; CHROMOSOMES ; SUBSET ; CYTOGENETIC ANALYSIS ; BREAKPOINTS ; MYCN-AMPLIFICATION ; function ; LOSSES ; HIGH-RESOLUTION ANALYSIS ; genomic ; GENOMIC ALTERATIONS ; 11Q ; CGH ANALYSIS ; DNA-COPY-NUMBER
    Abstract: The study of genomic alterations in neuroblastoma is of particular importance since several cytogenetic markers proved to be closely associated with the clinical phenotype. To disclose patterns of gains and losses, we performed high-resolution oligonucleotide array-based comparative genomic hybridization (aCGH). A total cohort of 90 patients was classified into 6 subsets according to tumor stage and outcome: Stages 1-3+ (with event), Stage 1-3- (no event), Stage 4+/-, and Stage 4S+/-. The aberration patterns in Stages 1-3- and 4S- tumors differed from all other groups as they were predominantly characterized by losses (3, 4, 14, X) and gains (7, 17) of whole chromosomes. However, 59/65 (91%) tumors of Stages 1-3+ or Stage 4 revealed numerous structural copy number alterations (sCNA). While deletions in chromosomes 1, 3, and I I discriminated outcome in Stage 4, there were no specific sCNA that distinguished tumor stage within the subgroup of unfavorable tumors. sCNA in 1p, 3p, 11q, 17q, or MYCN amplification (MNA) was seen among 22/24 patients who died, 10/12 with metastatic relapses, and 5/9 with local recurrences. Detailed breakpoint analyses on chromosomes 1, 3, 11, and 17 disclosed preferred breaking areas, although breakpoints were not identical. Amplifications were found in 18 patients and involved 2p24 (MYCN) and other segments of chromosome 2, as well as regions on chromosome arms 6q, 12q, and 17q. One single feature in 21q21.1 (BU678720, without known function yet) attracted particular attention since five patients showed a homozygous loss of this sequence. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat. (c) 2006 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 16958102
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  • 7
    Keywords: CANCER ; EXPRESSION ; GROWTH ; proliferation ; CELL ; Germany ; INHIBITION ; PATHWAY ; PATHWAYS ; NETWORK ; DEATH ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; ACTIVATION ; cell cycle ; CELL-CYCLE ; CYCLE ; ASSOCIATION ; chromosome ; LESIONS ; PROGRESSION ; gene expression ; DIFFERENCE ; CELL-DEATH ; MUTATION ; genetics ; COMPONENT ; MUTATIONS ; MALIGNANT-MELANOMA ; OVEREXPRESSION ; heredity ; B-RAF ; TRANSCRIPTS ; ONCOLOGY ; RE ; N-RAS MUTATIONS ; analysis ; cell death ; senescence ; ERK ; USA ; CELL-CYCLE ARREST ; SET ; apoptotic
    Abstract: We studied gene expression in 18 melanocytic nevi with and four nevi without the V600E mutation in the BRAF gene using HG-U133A 2.0 microarray with 22,277 transcripts. Data analysis revealed 92 genes up-regulated and 105 genes down-regulated in nevi with the mutation compared to nevi without mutation. Pathway analysis showed that differentially regulated genes mapped to 10 genetic networks. The major network included genes involved in cell death, cell cycle, and cellular growth and proliferation. Up-regulated genes in nevi with the mutation included CDKN2A, CDKN1C, and MITF; whereas down-regulated genes included those involved in apoptotic and other pathways. Principal component analysis identified 22 probe sets (20 genes) that caused separate segregation of nevi with and without mutations. In conclusion, our data showed differences in gene expression between nevi with and without the V600E BRAF mutation. Moreover, nevi with mutations showed overexpression of genes involved in melanocytic senescence and cell cycle inhibition. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat. (C) 2007 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 17696195
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  • 8
    Keywords: CANCER ; EXPRESSION ; CELL ; Germany ; IN-VIVO ; THERAPY ; DISEASE ; RISK ; GENE ; GENE-EXPRESSION ; GENES ; PATIENT ; ASSOCIATION ; DELETION ; COMPARATIVE GENOMIC HYBRIDIZATION ; gene expression ; DIFFERENCE ; NUMBER ; genetics ; leukemia ; DELETIONS ; REGION ; REGIONS ; HIGH-RISK ; CHILDREN ; CHRONIC MYELOGENOUS LEUKEMIA ; PROGNOSTIC FACTOR ; heredity ; ONCOLOGY ; CHILDHOOD ; THERAPIES ; PROGNOSTIC IMPACT ; CELL LYMPHOMA ; PROGNOSTIC-FACTOR ; USA ; LOSSES ; ARRAY-CGH ; PROFILE ; DERIVATIVE CHROMOSOME-9 ; EARLY TREATMENT RESPONSE ; INTRACHROMOSOMAL AMPLIFICATION ; TRANSLOCATION T(1/19)
    Abstract: In vivo response to initial therapy, as assessed by determination of minimal residual disease (MRD) after 5 and 12 weeks of treatment, has evolved as a strong prognostic factor in children with acute lymphoblastic leukemia (ALL) treated according to the BFM regime. Individual treatment response may be influenced by copy number alterations (CNA) leading to altered gene expression. We aimed to evaluate CNA using high-resolution array-comparative genomic hybridization (array-CGH) in different treatment-response groups. Leukemic genomic profiles of 25 standard risk (MRD-SR) and 25 high risk (MRD-HR) patients were compared. CNAs were found in 46/50 patients (92%). The most significant difference was a gain of 1q23-qter because of an unbalanced t(1; 19), found in 10/25 MRD-SR patients, but in none of the MRD-HR patients (P 〈 0.001). The most frequent Cl in the MRD-HR group were deletions of genomic regions harboring the immunoglobulin genes (1g), e.g., 2p11.2 in 60% of MRD-HR compared to 28% of MRD-SR (P = 0.045). Combining all 1g loci, significantly more MRD-HR than MRD-SR patients displayed deletions (17:8 patients, P = 0.02). Frequency of other CNAs, such as loss of 9p21 or gains of 21q, did not differ strongly between the two patient groups. This is the first study evaluating the clinical significance of CNA as detected by array-CGH in childhood ALL and the first to suggest that such analyses may provide clinically important data. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat. (C) 2008 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 18311775
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  • 9
    Keywords: Germany ; human ; DISEASE ; GENE ; PATIENT ; recombination ; SEQUENCE ; SEQUENCES ; DELETION ; ELEMENT ; PROBE ; PHENOTYPES ; AMPLIFICATION ; AGE ; MUTATION ; genetics ; DELETIONS ; MUTATIONS ; PHENOTYPE ; INDIVIDUALS ; CLINICAL-FEATURES ; HOMOLOGOUS RECOMBINATION ; JUNCTIONS ; SINGLE ; FEATURES ; ONSET ; JUNCTION ; 3 ; Genetic ; MEDICAL-CENTER
    Abstract: In this study, the breakpoints of six large intragenic deletions in the NF2 gene are determined, which had initially been detected by multiplex ligation-dependent probe amplification. While one breakpoint occurred within an exon, the remaining 11 lied in the corresponding flanking introns. Two of the deletions were most likely caused by nonallelic homologous recombination between Alu sequences, while the other four appeared to be the result of nonhomologous endjoining, possibly facilitated by rearrangement-promoting elements at the junctions in some cases. The clinical features of patients with large intragenic deletions and individuals with mutations affecting single or multiple nucleotides of the NF2 gene are relatively similar. However, patients with deletions of the 3' exons 15 and 16 of the NF2 gene did exhibit milder phenotypes, especially with respect to the age of disease onset. (c) 2009 Wiley-Liss, Inc.
    Type of Publication: Journal article published
    PubMed ID: 19924781
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  • 10
    Abstract: Multiple myeloma (MM) is proposed to consist of two main pathogenetic groups. Although hyperdiploid MM (HD) is characterized by multiple trisomies of odd chromosomes, in nonhyperdiploid MM (NHD), one of the recurrent primary immunoglobulin heavy chain (IGH) translocations and deletion of chromosome 13 can frequently be found. In this study, we analyzed gene-expression profiles of patients with previously untreated MM. Fifty-four genes were significantly differentially expressed between the two groups. NPM1 was upregulated in HD. The differential expression of 25 genes, including NPM1 and 13 ribosomal protein genes, was validated using a published gene expression data set. The overexpression of NPM1 in HD was further confirmed by quantitative real-time PCR and Western blotting. NPM1 was significantly overexpressed in HD as the result of a gain of chromosome 5. Insertions into exon 12 of NPM1 were not detected. NPM1 was localized to the nucleoli of MM cells. Furthermore, HD was associated with an overexpression of ribosomal protein genes, independent of their localization on the trisomic or other chromosomes. Our results indicate that the gain of chromosome 5 might play an important role in the pathogenesis of HD.
    Type of Publication: Journal article published
    PubMed ID: 20073075
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