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  • 1
    Keywords: CANCER ; CELLS ; EXPRESSION ; tumor ; carcinoma ; GENE ; GENE-EXPRESSION ; COMPLEXES ; BREAST-CANCER ; COMPARATIVE GENOMIC HYBRIDIZATION ; gene expression ; MUTATION ; METASTASIS ; SIGNALING PATHWAYS ; SOLID TUMORS ; PRIMARY TUMORS ; SUBTYPES ; GENETIC ALTERATIONS ; LYMPH-NODE METASTASES
    Abstract: Introduction: With the improvement of therapeutic options for the treatment of breast cancer, the development of brain metastases has become a major limitation to life expectancy in many patients. Therefore, our aim was to identify molecular markers associated with the development of brain metastases in breast cancer. Methods: Patterns of chromosomal aberrations in primary breast tumors and brain metastases were compared with array-comparative genetic hybridization (CGH). The most significant region was further characterized in more detail by microsatellite and gene-expression analysis, and finally, the possible target gene was screened for mutations. Results: The array CGH results showed that brain metastases, in general, display similar chromosomal aberrations as do primary tumors, but with a notably higher frequency. Statistically significant differences were found at nine different chromosomal loci, with a gain and amplification of EGFR (7p11.2) and a loss of 10q22.3-qter being among the most significant aberrations in brain metastases (P 〈 0.01; false discovery rate (fdr) 〈 0.04). Allelic imbalance (AI) patterns at 10q were further verified in 77 unmatched primary tumors and 21 brain metastases. AI at PTEN loci was found significantly more often in brain metastases (52%) and primary tumors with a brain relapse (59%) compared with primary tumors from patients without relapse (18%; P = 0.003) or relapse other than brain tumors (12%; P = 0.006). Loss of PTEN was especially frequent in HER2-negative brain metastases (64%). Furthermore, PTEN mRNA expression was significantly downregulated in brain metastases compared with primary tumors, and PTEN mutations were frequently found in brain metastases. Conclusions: These results demonstrate that brain metastases often show very complex genomic-aberration patterns, suggesting a potential role of PTEN and EGFR in brain metastasis formation
    Type of Publication: Journal article published
    PubMed ID: 22429330
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  • 2
    Keywords: CANCER ; HEPATOCELLULAR-CARCINOMA ; GENE ; NERVOUS-SYSTEM ; POOR-PROGNOSIS ; RANDOMIZED-TRIAL ; OLIGODENDROGLIAL TUMORS ; IDH1 mutation ; VINCRISTINE CHEMOTHERAPY ; BRAIN-TUMOR GROUP
    Abstract: There is a lack of relevant prognostic and predictive factors in neurooncology besides mutation of isocitrate dehydrogenase 1, codeletion of 1p/19q and promoter hypermethylation of O (6) -methylguanine-DNA-methyltransferase. More importantly, there is limited translation of these factors into clinical practice. The cancer genome atlas data and also clinical correlative analyses suggest a pivotal role for the epidermal growth factor receptor /protein kinase B/mammalian target of rapamycin (mTOR) pathway in both biology and the clinical course of gliomas. However, attempts to stratify gliomas by activating alterations in this pathway have failed thus far. The tumors of 40 patients with WHO grade II gliomas without immediate postoperative genotoxic treatment and known progression and survival status at a median follow-up of 12.2 years were analyzed for expression of the mTOR complex 2 downstream target N-myc downstream regulated gene (NDRG)1 using immunohistochemistry. Baseline characteristics for NDRG1 absent/low versus moderate/high patients were similar. Time to reintervention was significantly longer in the NDRG1 group (P = 0.026). NDRG1 may become a novel biomarker to guide the decision which WHOA degrees II glioma patients may be followed without postsurgical intervention and which patients should receive genotoxic treatment early on. Validation of this hypothesis will be possible with the observational arm of the RTOG 9802 and the pretreatment step of the EORTC 22033/26032 trials.
    Type of Publication: Journal article published
    PubMed ID: 24395351
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  • 3
    Keywords: CELL LUNG-CANCER ; GENE ; PROTEINS ; BREAST-CANCER ; METASTASIS ; DISSEMINATED TUMOR-CELLS ; IMBALANCES ; METHYLATION ; TUMORIGENESIS ; CHROMOSOME 4Q
    Abstract: For better lung cancer diagnosis and therapy, early detection markers of tumor dissemination are urgently needed, as most lung cancers do not show symptoms until extensive metastasis formation has already taken place. Our previous studies showed that in non-small cell lung cancer (NSCLC) early tumor dissemination is associated with a loss of chromosome 4q12-q32 and the presence of disseminated tumor cells (DTC) in the bone marrow. In order to identify the potential target gene in this region, a screen for methylation-dependent expression was performed. Lung cancer cell lines showing a loss of 4q as well as a normal bronchial epithelial cell line as control were treated with 5-aza-2'-deoxycytidine (5-aza-CdR) followed by expression profiling. Seven genes within the 4q target region, which have been associated with a positive DTC status before were found to be regulated by hypermethylation. QRT-PCR in an independent sample set identified HERC5 as a potential target gene. Quantitative methylation analysis of these lung tissue samples revealed that HERC5 promoter hypermethylation was significantly associated with positive DTC status (p=0.020) and occurrence of brain metastases (p=0.015). In addition, hypermethylation of the HERC5 promoter in NSCLC was identified as a predictor for poor survival for Stage I adenocarcinoma patients (p=0.022) and also for poor overall survival in metastatic lung cancer patients (p=0.028). In conclusion, HERC5 may function as a prognostic marker and is associated with tumor dissemination in lung cancer. What's new? In order to improve the diagnosis and therapy of lung cancer, early biomarkers of tumor dissemination are urgently needed. In this study, the authors found that the HERC5 gene on chromosome 4 may be involved in regulating the spread of non-small cell lung cancer (NSCLC) tumors. In cases where the promoter region of HERC5 was hypermethylated, the number of disseminated tumor cells (DTC) and metastases increased, and survival decreased. HERC5 may thus be a new metastasis-suppressor gene, and its methylation and expression status may provide prognostic biomarkers for NSCLC.
    Type of Publication: Journal article published
    PubMed ID: 25353388
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  • 4
    Keywords: CANCER ; radiotherapy ; SURVIVAL ; tumor ; Germany ; neoplasms ; THERAPY ; FOLLOW-UP ; DISEASE ; GENE ; TISSUE ; TUMORS ; PATIENT ; chromosome ; PROGRESSION ; AMPLIFICATION ; DESIGN ; resistance ; STRESS ; chemotherapy ; RESECTION ; PRODUCT ; MULTIVARIATE ; PROGNOSTIC VALUE ; sensitivity ; experimental design ; 1p ; CHROMOSOMES ; GENE-PRODUCT ; ONCOLOGY ; RE ; PRODUCTS ; THERAPIES ; END ; GRADE ; biomarker ; oligodendroglioma ; ANAPLASTIC OLIGODENDROGLIOMAS ; HISTOLOGY ; USA ; LOSSES ; OLIGODENDROGLIAL TUMORS ; cancer research ; EXTENT ; - ; PROGRESSION-FREE SURVIVAL ; outcome ; PHASE-III TRIAL
    Abstract: Purpose: The combined loss of genetic material on chromosomes 1p and 19q is strongly associated with favorable outcome in patients with WHO grade 3 anaplastic oligodendroglial tumors. The prognostic value of 1p/19q loss in WHO grade 2 oligodendroglial tumors is less well defined. Importantly, the possible effect of combined 1p/19q loss has not been studied in patients who were! not treated with radiotherapy or chemotherapy. Experimental Design: Seventy-six patients with oligodendroglioma (n = 33), oligoastrocytoma (n = 30), anaplastic oligodendroglioma (n = 6), or anaplastic oligoastrocytoma (n = 7) were identified who had not received radiotherapy or chemotherapy after their first operation until the end of follow-up or until the first progression and had tissue for 1p/19q status available. 1p/19q status was assessed by multiplex ligation - dependent probe amplification. Results: After a median follow-up of 3.8 years, progressive disease was documented in 34 patients. The estimated median progression-free survival was 4.6 years. Fifty-eight of the 76 patients had a combined loss of 1p and 19q. The absence or presence of combined 1p/19q loss was not prognostic for progression-free survival using multivariate adjustment for histology, extent of resection, and gender. Conclusions: Combined 1p/19q loss is not a sensitive prognostic biomarker in patients with oligodendroglial tumors who do not receive radiotherapy or chemotherapy. The gene products lost as a consequence of this codeletion may include mediators of resistance to genotoxic therapies. Alternatively, 1p/19q loss might be an early oncogenic lesion promoting the formation of glial neoplasms, which retain high sensitivity to genotoxic stress
    Type of Publication: Journal article published
    PubMed ID: 18056167
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  • 5
    Keywords: EXPRESSION ; IN-VITRO ; tumor ; GENE ; DOWN-REGULATION ; STEM-CELLS ; NATURAL-KILLER-CELLS ; GLIOMA-CELLS ; MALIGNANT GLIOMA ; IFN-BETA
    Abstract: Immunotherapy targeting glioblastoma initiating cells (GIC) is considered a promising strategy. However, GIC are prone to evade immune response and there is a need for potent adjuvants. IFN-beta might enhance the immune response and here we define its net effect on the innate immunogenicity of GIC. The transcriptomes of GIC treated with IFN-beta and controls were assessed by microarray-based expression profiling for altered expression of immune regulatory genes. Several genes involved in adaptive and innate immune responses were regulated by IFN-beta. We validated these results using reverse transcription (RT)-PCR and flow cytometry for corresponding protein levels. The up-regulation of the NK cell inhibitory molecules HLA-E and MHC class I was balanced by immune stimulating effects including the up-regulation of nectin-2. In 3 out of 5 GIC lines tested we found a net immune stimulating effect of IFN-beta in cytotoxicity assays using NKL cells as effectors. IFN-beta therefore warrants further investigation as an adjuvant for immunotherapy targeting GIC.
    Type of Publication: Journal article published
    PubMed ID: 26441059
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  • 6
    Keywords: brain ; RECEPTOR ; EXPRESSION ; Germany ; PATHWAY ; SYSTEM ; GENE ; GENE-EXPRESSION ; GENES ; LINES ; DNA ; MESSENGER-RNA ; synaptic plasticity ; PATTERNS ; MUTATION ; MUTATIONS ; RE ; NEURONS ; conditional mutagenesis ; D1 DOPAMINE-RECEPTOR ; MEDIUM SPINY NEURONS ; RAT STRIATUM
    Abstract: Background: Dopamine-activated signaling regulates locomotor and emotional responses and alterations in dopamine-signaling are responsible of several psychomotor disorders. In order to identify specific functions of these pathways, the Cre/loxP system has been used. Here, we describe the generation and the characterization of a transgenic mouse line expressing the Cre recombinase in dopaminoceptive neurons. To this purpose, we used as expression vector a 140 kb yeast artificial chromosome (YAC) containing the dopamine DI receptor gene (DrdIa). Results: In the chosen line, DICre, the spatio-temporal pattern of Cre expression closely recapitulated that of the endogenous DrdIa gene, as assessed by immunohistological approaches in embryonic and adult stages. Efficiency of recombination was confirmed by crossing DICre with three different loxP lines (CrebI(loxP), CaMKIVloxP and GR(loxP)) and with the R26R reporter. In the three loxP lines studied, recombination was restricted to the area of Cre expression. Conclusion: In view of the patterns of recombination restricted to the major dopaminoceptive regions as seen in the context of the CREB, CaMKIV and GR mutations, the DICre line will be a useful tool to dissect the contributions of specific genes to biological processes involving dopamine signaling
    Type of Publication: Journal article published
    PubMed ID: 17201924
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  • 7
    Keywords: EXPRESSION ; Germany ; human ; KINASE ; GENE ; GENE-EXPRESSION ; PROTEIN ; SAMPLE ; transcription ; DRUG ; MICE ; MECHANISM ; mechanisms ; BINDING ; PHOSPHORYLATION ; PROTEIN-KINASE ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; TARGET ; CREB ; ELEMENT-BINDING PROTEIN ; NO ; TRANSCRIPTION FACTORS ; gene expression ; HUMANS ; PROMOTER ; REGION ; REGIONS ; sensitization ; sensitivity ; BEHAVIOR ; BINDING PROTEIN ; molecular ; RE ; DEFICIENT MICE ; MICE LACKING ; NEURONS ; ABLATION ; PROMOTER POLYMORPHISM ; ADDICTION ; conditioned place preference ; LEVEL ; FOREBRAIN ; USA ; LOSSES ; PROMOTER REGION ; NOV ; ACAD ; association study ; striatum ; response ; PLASTICITY ; NUCLEOTIDE ; CaMKIV ; DELTA-FOSB ; EMOTIONAL STIMULI ; NEURAL ACTIVITY ; NUCLEUS-ACCUMBENS
    Abstract: The persistent nature of addiction has been associated with activity-induced plasticity of neurons within the striatum and nucleus accumbens (NAc). To identify the molecular processes leading to these adaptations, we performed Cre/loxP-mediated genetic ablations of two key regulators of gene expression in response to activity, the Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) and its postulated main target, the cAMP-responsive element binding protein (CREB). We found that acute cocaine-induced gene expression in the striatum was largely unaffected by the loss of CaMKIV. On the behavioral level, mice lacking CaMKIV in dopaminoceptive neurons displayed increased sensitivity to cocaine as evidenced by augmented expression of locomotor sensitization and enhanced conditioned place preference and reinstatement after extinction. However, the loss of CREB in the forebrain had no effect on either of these behaviors, even though it robustly blunted acute cocaine-induced transcription. To test the relevance of these observations for addiction in humans, we performed an association study of CAMK4 and CREB promoter polymorphisms with cocaine addiction in a large sample of addicts. We found that a single nucleotide polymorphism in the CAMK4 promoter was significantly associated with cocaine addiction, whereas variations in the CREB promoter regions did not correlate with drug abuse. These findings reveal a critical role for CaMKIV in the development and persistence of cocaine-induced behaviors, through mechanisms dissociated from acute effects on gene expression and CREB-dependent transcription
    Type of Publication: Journal article published
    PubMed ID: 19001277
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