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  • EXPRESSION  (6)
  • 1
    Keywords: CANCER ; EXPRESSION ; GENE ; DIFFERENTIATION ; VARIANTS ; DISCOVERY ; ALPHA ; ALIGNMENT ; ESTROGEN
    Abstract: Meningiomas are among the most frequent intracranial tumors. The secretory variant of meningioma is characterized by glandular differentiation, formation of intracellular lumina and pseudopsammoma bodies, expression of a distinct pattern of cytokeratins and clinically by pronounced perifocal brain edema. Here we describe whole-exome sequencing analysis of DNA from 16 secretory meningiomas and corresponding constitutional tissues. All secretory meningiomas invariably harbored a mutation in both KLF4 and TRAF7. Validation in an independent cohort of 14 secretory meningiomas by Sanger sequencing or derived cleaved amplified polymorphic sequence (dCAPS) assay detected the same pattern, with KLF4 mutations observed in a total of 30/30 and TRAF7 mutations in 29/30 of these tumors. All KLF4 mutations were identical, affected codon 409 and resulted in a lysine to glutamine exchange (K409Q). KLF4 mutations were not found in 89 non-secretory meningiomas, 267 other intracranial tumors including gliomas, glioneuronal tumors, pituitary adenomas and metastases, 59 peripheral nerve sheath tumors and 52 pancreatic tumors. TRAF7 mutations were restricted to the WD40 domains. While KLF4 mutations were exclusively seen in secretory meningiomas, TRAF7 mutations were also observed in 7/89 (8 %) of non-secretory meningiomas. KLF4 and TRAF7 mutations were mutually exclusive with NF2 mutations. In conclusion, our findings suggest an essential contribution of combined KLF4 K409Q and TRAF7 mutations in the genesis of secretory meningioma and demonstrate a role for TRAF7 alterations in other non-NF2 meningiomas.
    Type of Publication: Journal article published
    PubMed ID: 23404370
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  • 2
    Keywords: EXPRESSION ; radiotherapy ; SURVIVAL ; PROGRESSION ; ASTROCYTOMAS ; GLIOMAS ; MULTIFORME ; NEWLY-DIAGNOSED GLIOBLASTOMA ; EGFRVIII ; NEUROONCOLOGY
    Abstract: The epidermal growth factor receptor vIII mutant (EGFRvIII) is found in approximately 50% of all EGFR-amplified glioblastomas and constitutes a tumor-specific therapeutic target. To assess molecular testing approaches and the prognostic role of EGFRvIII in patients treated according to current standards of care, we compared different EGFRvIII detection methods and correlated EGFRvIII status with outcome in a prospective patient cohort of the German Glioma Network. In total, 184 newly diagnosed glioblastoma patients were investigated for EGFR amplification and for expression of EGFR and EGFRvIII by immunohistochemistry. Further, the EGFRvIII status was additionally studied by multiplex ligation-dependent probe amplification (MLPA) analysis and reverse transcription-PCR (RT-PCR). Immunohistochemistry demonstrated EGFRvIII in 34 of 184 patients (18%). RT-PCR or MLPA analysis detected 4 additional EGFRvIII-positive patients. Overall, RT-PCR and immunohistochemistry were more sensitive for EGFRvIII detection than MLPA. EGFRvIII status was not associated with progression-free and overall survival. EGFRvIII also had no prognostic significance in the subgroup of patients who were free from progression after concomitant radiochemotherapy and thus would be eligible for the ongoing ACT IV EGFRvIII vaccination trial. Age, extent of resection, and O6 -methylguanine DNA methyltransferase (MGMT) promoter methylation status appeared to be less prognostic in EGFRvIII-positive patients. Thus, EGFRvIII positivity is not a major negative prognostic factor in glioblastoma patients treated according to current standards of care. Data from phase II EGFRvIII-targeted vaccination trials compare favorably with the present contemporary results, supporting the further exploration of EGVRvIII vaccination in newly diagnosed glioblastoma. (c) 2013 Wiley Periodicals, Inc.
    Type of Publication: Journal article published
    PubMed ID: 24614983
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  • 3
    Keywords: EXPRESSION ; AGENTS ; human ; GENE ; PROTEIN ; DIFFERENTIATION ; TISSUE ; MICE ; MECHANISM ; INDUCTION ; TISSUES ; KERATINOCYTES ; mechanisms ; SKIN ; SEQUENCE ; SEQUENCES ; STAGE ; TRANSGENIC MICE ; IDENTIFICATION ; PROMOTER ; transgenic ; REGION ; FRANCE ; hyperproliferation ; epidermis ; TERMINAL DIFFERENTIATION ; LAYER ; MAMMALIAN-TISSUES ; HASSALLS CORPUSCLES ; FOLLICLE ; HAIR-FOLLICLES ; HUMAN TISSUES ; INNER-ROOT-SHEATH ; AGENT ; PATTERN ; HAIR FOLLICLE ; corneodesmosin ; CORNIFIED EPITHELIA ; GENE PROMOTER ; hyperkeratosis ; KERATINOCYTE DIFFERENTIATION ; promoter regions ; PSORIASIS SUSCEPTIBILITY ; REPORTER GENE ; S GENE ; STRATUM-CORNEUM
    Abstract: Corneodesmosin (CDSN) is a desmosomal protein expressed in the epidermis during the late stages of differentiation and in the inner root sheath of hair follicles. The homophilic adhesive properties of the protein suggest that it reinforces keratinocyte cohesion in the upper layers of the epidermis (stratum granulosum and stratum corneum). In this study, we analyzed the expression of the CDSN gene in 16 human tissues. We confirmed the closely restricted expression pattern of CSDN. Indeed, apart from the skin, the mRNA was significantly detected only in the placenta and the thymus. As a step in elucidating the mechanisms of tissue-specific expression, transgenic mice bearing a 4.2 kb fragment of the human CSDN gene promoter linked to the LacZ gene were generated. The reporter-gene expression was detected in special areas of the inner root sheath of the hair follicles and the hair medulla but not in the epidermis. Induction of epidermis hyperproliferation however either by pharmacological agents or by wounding led to strong expression of the reporter gene in the keratinocytes of the stratum granulosum and the parakeratotic corneocytes of the stratum corneum. The data suggest that the genomic sequences and/or regulating factors responsible for the cell-specific expression of the human CDSN gene in the normal hair follicle as well as in the hyperproliferative epidermis are different from those necessary for expression in the normal epidermis
    Type of Publication: Journal article published
    PubMed ID: 15086560
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  • 4
    Keywords: RECEPTOR ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; INVASION ; tumor ; CELL ; Germany ; PATHWAY ; PATHWAYS ; SYSTEM ; incidence ; GENE ; GENES ; meningioma ; SURGERY ; TRANSDUCTION ; ACTIVATION ; MECHANISM ; mechanisms ; DYNAMICS ; cell cycle ; CELL-CYCLE ; CYCLE ; signal transduction ; chromosome ; SIGNAL ; ACID ; TARGET ; hormone ; PROGRESSION ; COMPARATIVE GENOMIC HYBRIDIZATION ; MUTATION ; genetics ; SIGNAL-TRANSDUCTION ; inactivation ; PATHOGENESIS ; DAMAGE ; HEREDITARY ; MUTATIONS ; STRATEGIES ; TARGETS ; FUTURE ; RECEPTORS ; CYCLE CONTROL ; INITIATION ; 1p ; CHROMOSOMES ; molecular ; MOLECULAR-MECHANISM ; review ; TUMOR-SUPPRESSOR ; SUPPRESSOR GENE ; MALIGNANT PROGRESSION ; development ; MOLECULAR-MECHANISMS ; SUPPRESSOR ; MOLECULAR-GENETICS ; EVENTS ; telomere ; TELOMERASE ACTIVITY ; USA ; HORMONES ; LOSSES ; STEROID-HORMONES ; MOLECULAR PATHOGENESIS ; NERVOUS-SYSTEM TUMORS ; HUMAN BRAIN-TUMORS ; GRADING SYSTEM ; genomic ; GENETIC ALTERATION ; molecular genetics ; TUMOR-SUPPRESSOR GENES ; MAINTENANCE ; cell cycle control ; GROWTH-FACTORS ; refractory ; CASCADE ; CLINICAL-APPLICATIONS ; INTEGRITY ; ANAPLASTIC MENINGIOMAS ; meningioma progression ; meningioma therapy ; NF2 ; NF2 GENE ; RADIATION-INDUCED MENINGIOMAS ; SPORADIC MENINGIOMAS
    Abstract: TO REVIEW OUR CURRENT understanding of the molecular pathogenesis of meningiomas, to suggest topics for future investigations, and to present perspectives for clinical application. Significant progress has been made in recent years in delineating the molecular mechanisms involved in meningioma formation, growth, and malignant progression. However, many questions remain unanswered. Mutations in the NF2 gene probably account for the formation of more than half of all meningiomas. On the other hand, the molecular events underlying the initiation of meningiomas without NF2 mutations have yet to be identified. Investigating hereditary conditions associated with an increased meningioma incidence and the mechanisms underlying the development of radiation-induced meningiomas could potentially yield relevant insights. Meningioma growth is sustained by the dysregulated expression of steroid hormones, growth factors, their receptors, and activation of signal transduction cascades. The underlying genetic causes are unknown. Malignant progression of meningiomas probably involves the inactivation of tumor suppressor genes on chromosomes 1p, 9p, 10q, and 14q. However, with the possible exception of INK4A/INK4B, the actual targets of these chromosomal losses have remained largely elusive. Cell cycle dysregulation and telomerase activation have been recognized as important steps in meningioma progression. Telomere dynamics, cell cycle control, and the mechanisms responsible for deoxyribonucleic acid damage control are tightly interwoven. Investigating genes involved in the maintenance of genomic integrity might significantly deepen the understanding of meningioma progression. An area that has received relatively little attention thus far is the genetic background of meningioma spread and invasion. Possible clinical applications of the molecular data available may include a meningioma grading system based on genetic alterations, as well as therapeutic strategies for refractory meningiomas aimed at interfering with signal transduction pathways
    Type of Publication: Journal article published
    PubMed ID: 17460514
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  • 5
    Keywords: CANCER ; EXPRESSION ; POPULATION ; RISK ; TUMORS ; PROFILES ; GENOME-WIDE ASSOCIATION ; KORA
    Abstract: We have previously identified tagSNPs at 8q24.21 influencing glioma risk. We have sought to fine-map the location of the functional basis of this association using data from four genome-wide association studies, comprising a total of 4147 glioma cases and 7435 controls. To improve marker density across the 700 kb region, we imputed genotypes using 1000 Genomes Project data and high-coverage sequencing data generated on 253 individuals. Analysis revealed an imputed low-frequency SNP rs55705857 (P = 2.24 x 10(-38)) which was sufficient to fully capture the 8q24.21 association. Analysis by glioma subtype showed the association with rs55705857 confined to non-glioblastoma multiforme (non-GBM) tumours (P = 1.07 x 10(-67)). Validation of the non-GBM association was shown in three additional datasets (625 non-GBM cases, 2412 controls; P = 1.41 x 10(-28)). In the pooled analysis, the odds ratio for low-grade glioma associated with rs55705857 was 4.3 (P = 2.31 x 10(-94)). rs55705857 maps to a highly evolutionarily conserved sequence within the long non-coding RNA CCDC26 raising the possibility of direct functionality. These data provide additional insights into the aetiological basis of glioma development.
    Type of Publication: Journal article published
    PubMed ID: 23399484
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  • 6
    Keywords: CANCER ; EXPRESSION ; TUMORS ; NERVOUS-SYSTEM ; GLIOMA ; temozolomide ; TELOMERASE ACTIVITY ; GENOME-WIDE ASSOCIATION ; SECONDARY GLIOBLASTOMAS ; PHASE-3 TRIAL
    Abstract: Background. Activating somatic mutations in the promoter region of the telomerase reverse transcriptase gene (TERT) have been detected in several cancers. In this study we investigated the TERT promoter mutations and their impact on patient survival in World Health Organization grade IV glioblastoma multiforme (GBM). Methods. The TERT core promoter region containing the previously described mutations and a common functional polymorphism (rs2853669) was sequenced in tumors and blood samples from 192 GBM patients. O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was assessed by pyrosequencing in 177 (92.2%) cases. Relevant clinical data were obtained from a prospectively maintained electronic database. Results. We detected specific (-124 C〉T and -146 C〉T) TERT promoter mutations in 143/178 (80.3%) primary GBM and 4/14 (28.6%) secondary GBM (P〈 .001). The presence of TERT mutations was associated with poor overall survival, and the effect was confined to the patients who did not carry the variant G-allele for the rs2853669 polymorphism. An exploratory analysis suggested that TERT mutations might be prognostic only in patients who had incomplete resections and no temozolomide chemotherapy. Conclusions. In this study, specific TERT promoter mutations were markers of primary GBM and predicted patient survival in conjunction with a common functional polymorphism. The prognostic impact of TERT mutations was absent in patients with complete resections and temozolomide chemotherapy. If confirmed in additional studies, these findings may have clinical implications, that is, TERT mutations appear to characterize tumors that require aggressive treatment.
    Type of Publication: Journal article published
    PubMed ID: 25140036
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