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  • DKFZ Publication Database  (97)
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    Keywords: CELLS ; EXPRESSION ; Germany ; SYSTEMS ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; SACCHAROMYCES-CEREVISIAE ; METABOLISM ; COMPLEX ; COMPLEXES ; SEQUENCE ; METABOLITES ; gene expression ; ESCHERICHIA-COLI ; DATABASE ; OXYGEN ; CLUSTER ; MATRIX ; SYNTHETASE ; EXTRACTION ; LEVEL ; ENZYME ; TECHNOLOGY ; EXPRESSION PATTERNS ; CHAIN AMINO-ACIDS ; K-12
    Abstract: Background: Microarray technology produces gene expression data on a genomic scale for an endless variety of organisms and conditions. However, this vast amount of information needs to be extracted in a reasonable way and funneled into manageable and functionally meaningful patterns. Genes may be reasonably combined using knowledge about their interaction behaviour. On a proteomic level, biochemical research has elucidated an increasingly complete image of the metabolic architecture, especially for less complex organisms like the well studied bacterium Escherichia coli. Results: We sought to discover central components of the metabolic network, regulated by the expression of associated genes under changing conditions. We mapped gene expression data from E. coli under aerobic and anaerobic conditions onto the enzymatic reaction nodes of its metabolic network. An adjacency matrix of the metabolites was created from this graph. A consecutive ones clustering method was used to obtain network clusters in the matrix. The wavelet method was applied on the adjacency matrices of these clusters to collect features for the classifier. With a feature extraction method the most discriminating features were selected. We yielded network sub-graphs from these top ranking features representing formate fermentation, in good agreement with the anaerobic response of heterofermentative bacteria. Furthermore, we found a switch in the starting point for NAD biosynthesis, and an adaptation of the l-aspartate metabolism, in accordance with its higher abundance under anaerobic conditions. Conclusion: We developed and tested a novel method, based on a combination of rationally chosen machine learning methods, to analyse gene expression data on the basis of interaction data, using a metabolic network of enzymes. As a case study, we applied our method to E. coli under oxygen deprived conditions and extracted physiologically relevant patterns that represent an adaptation of the cells to changing environmental conditions. In general, our concept may be transferred to network analyses on biological interaction data, when data for two comparable states of the associated nodes are made available
    Type of Publication: Journal article published
    PubMed ID: 16524469
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  • 4
    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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  • 5
    Keywords: ENVIRONMENT ; SPECTRA ; CELLS ; EXPRESSION ; GROWTH ; CELL ; Germany ; PATHWAY ; PATHWAYS ; INFORMATION ; SYSTEM ; SYSTEMS ; GENE ; GENE-EXPRESSION ; GENOME ; microarray ; SACCHAROMYCES-CEREVISIAE ; METABOLISM ; DOWN-REGULATION ; treatment ; culture ; PATTERNS ; gene expression ; MICROARRAY DATA ; ESCHERICHIA-COLI ; UP-REGULATION ; OXYGEN ; CLUSTERS ; TRANSCRIPTIONAL REGULATION ; CLUSTER ; RE ; PRODUCTS ; HYDROGEN-PEROXIDE ; EXCRETION ; LEVEL ; methods ; PROFILES ; EXPRESSION PROFILES ; technique ; uptake ; E ; SPECTRUM ; microbiology ; image processing ; TOPOLOGY ; METABOLIC PATHWAYS ; SALMONELLA-TYPHIMURIUM ; ADAPTIVE RESPONSE ; ANAEROBIC RESPIRATION ; DEOXYRIBONUCLEOTIDE SYNTHESIS ; FUMARATE REDUCTASE ; MULTIORGANISM DATABASE
    Abstract: Background: Biochemical investigations over the last decades have elucidated an increasingly complete image of the cellular metabolism. To derive a systems view for the regulation of the metabolism when cells adapt to environmental changes, whole genome gene expression profiles can be analysed. Moreover, utilising a network topology based on gene relationships may facilitate interpreting this vast amount of information, and extracting significant patterns within the networks. Results: Interpreting expression levels as pixels with grey value intensities and network topology as relationships between pixels, allows for an image-like representation of cellular metabolism. While the topology of a regular image is a lattice grid, biological networks demonstrate scale-free architecture and thus advanced image processing methods such as wavelet transforms cannot directly be applied. In the study reported here, one-dimensional enzyme-enzyme pairs were tracked to reveal sub-graphs of a biological interaction network which showed significant adaptations to a changing environment. As a case study, the response of the hetero-fermentative bacterium E. coli to oxygen deprivation was investigated. With our novel method, we detected, as expected, an up-regulation in the pathways of hexose nutrients up-take and metabolism and formate fermentation. Furthermore, our approach revealed a down-regulation in iron processing as well as the up-regulation of the histidine biosynthesis pathway. The latter may reflect an adaptive response of E. coli against an increasingly acidic environment due to the excretion of acidic products during anaerobic growth in a batch culture. Conclusion: Based on microarray expression profiling data of prokaryotic cells exposed to fundamental treatment changes, our novel technique proved to extract system changes for a rather broad spectrum of the biochemical network
    Type of Publication: Journal article published
    PubMed ID: 17488495
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  • 6
    Abstract: Polymorphisms in genes involved in DNA repair, steroid hormone biosynthesis/metabolism/signaling, folate metabolism as well as cell growth are prime candidates for possible associations with breast and ovarian cancer risk in women with an inherited predisposition. We investigated 29 polymorphisms in 20 genes encoding key proteins of the above four biological pathways for their breast and ovarian cancer risk modifying effect in Polish women harboring BRCA1 founder mutations. Of the analyzed genes, ERCC2, XRCC1, XRCC2, XRCC3 and Lig4 participate in DNA repair, TP53 in cell cycle check point control, AIB1, AR, COMT, CYP11A1, CYP17A1, CYP19A1, HSD17 and PGR in steroid hormone biosynthesis/metabolism/signaling, TYMS in folate metabolism and HER2, IL6, LRP1, TGFB and TGFBR1 affect cell growth. Using validated methods, we genotyped 319 breast cancer cases, 146 ovarian cancer cases and 290 unaffected controls, all of whom harbored one of three causative mutations in BRCA1. Our results revealed no association of any of the investigated polymorphisms with BRCA1-associated breast or ovarian cancer risk. Thus, it appears that these polymorphisms do not influence disease risk in Polish women carrying one of the three common BRCA1 founder mutations.
    Type of Publication: Journal article published
    PubMed ID: 19360465
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  • 7
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; transcription ; ACTIVATION ; MUTATIONS ; POLYMERASE CHAIN-REACTION ; real-time PCR ; C-KIT ; IMATINIB MESYLATE ; THERAPEUTIC TARGET ; NERVE SHEATH TUMOR ; WILD-TYPE GISTS
    Abstract: Background: Gastrointestinal stromal tumors (GIST) represent the most common mesenchymal tumors of the gastrointestinal tract. About 85% carry an activating mutation in the KIT or PDGFRA gene. Approximately 10% of GIST are so-called wild type GIST (wt-GIST) without mutations in the hot spots. In the present study we evaluated appropriate reference genes for the expression analysis of formalin-fixed, paraffin-embedded and fresh frozen samples from gastrointestinal stromal tumors. We evaluated the gene expression of KIT as well as of the alternative receptor tyrosine kinase genes FLT3, CSF1-R, PDGFRB, AXL and MET by qPCR. wt-GIST were compared to samples with mutations in KIT exon 9 and 11 and PDGFRA exon 18 in order to evaluate whether overexpression of these alternative RTK might contribute to the pathogenesis of wt-GIST. Results: Gene expression variability of the pooled cDNA samples is much lower than the single reverse transcription cDNA synthesis. By combining the lowest variability values of fixed and fresh tissue, the genes POLR2A, PPIA, RPLPO and TFRC were chosen for further analysis of the GIST samples. Overexpression of KIT compared to the corresponding normal tissue was detected in each GIST subgroup except in GIST with PDGFRA exon 18 mutation. Comparing our sample groups, no significant differences in the gene expression levels of FLT3, CSF1R and AXL were determined. An exception was the sample group with KIT exon 9 mutation. A significantly reduced expression of CSF1R, FLT3 and PDGFRB compared to the normal tissue was detected. GIST with mutations in KIT exon 9 and 11 and in PDGFRA exon 18 showed a significant PDGFRB downregulation. Conclusions: As the variability of expression levels for the reference genes is very high comparing fresh frozen and formalin-fixed tissue there is a strong need for validation in each tissue type. None of the alternative receptor tyrosine kinases analyzed is associated with the pathogenesis of wild-type or mutated GIST. It remains to be clarified whether an autocrine or paracrine mechanism by overexpression of receptor tyrosine kinase ligands is responsible for the tumorigenesis of wt-GIST
    Type of Publication: Journal article published
    PubMed ID: 21171987
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  • 8
    Abstract: BACKGROUND: Obliterative bronchiolitis poses a primary obstacle for long-term survival of lung transplant recipients and manifests clinically as bronchiolitis obliterans syndrome (BOS). Establishing a molecular level screening method to detect BOS-related proteome changes before its diagnosis by forced expiratory volume surrogate marker criteria was the main objective of this study. METHODS: Bronchoalveolar lavage was performed in 82 lung transplant recipients (48/34 with/without known BOS development) at different time points between 12 and 48 months after lung transplantation. A mass spectrometry-based method was devised to generate bronchoalveolar lavage fluid proteome profiles that were screened for BOS-specific alterations. Statistically significant marker peptides and proteins were identified and validated by in-gel digestion, tandem mass spectrometric sequencing, and quantitative immunoassays. RESULTS: Among the panel of statistically significant markers were Clara cell protein, calgranulin A, human neutrophil peptides, and the antimicrobial agent histatin. To assess their clinical relevance, a highly sensitive and specific classifier model was developed. Positive BOS classification by monitoring of seven polypeptides correlated strongly with a significant decrease in BOS-free time. Thus, it was possible to detect high-risk patients early on in the pathogenetic process. CONCLUSIONS: Monitoring the bronchoalveolar lavage fluid levels of seven polypeptides detected by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry allows a reliable prediction of early BOS using a Random Forest decision tree-based classifier model. The high accuracy of this robust model and its synergistic potential in combination with established forced expiratory volume-based diagnostics could make it an effective tool to supplement the current diagnostic regime after multicentric validation.
    Type of Publication: Journal article published
    PubMed ID: 21716170
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  • 9
    Keywords: DISTINCT ; GENE ; BREAST-CANCER ; COPY-NUMBER ; SONIC HEDGEHOG ; GERMLINE ; LI-FRAUMENI-SYNDROME ; ACUTE MYELOID-LEUKEMIA ; telomere length ; FAMILIAL SYNDROME
    Abstract: 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 TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acutemyeloid leukemia. These findings connect p53 status and chr
    Type of Publication: Journal article published
    PubMed ID: 22265402
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  • 10
    Keywords: EXPRESSION ; TUMORS ; ABERRATIONS ; METHYLATION ; EMBRYONIC STEM-CELLS ; MULTIFORME ; HIGH-GRADE GLIOMAS ; TELOMERES ; INTEGRATED GENOMIC ANALYSIS ; ATRX
    Abstract: Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases(1-4). To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (alpha-thalassaemia/mental retardation syndrome X-linked)(5) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres(6,7), were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis
    Type of Publication: Journal article published
    PubMed ID: 22286061
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