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  • 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: 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: 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 ; 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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