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  • 1
    In: Neuropathology and Applied Neurobiology, October 2015, Vol.41(6), pp.733-742
    Description: BRAF V600E mutation, a marker of papillary craniopharyngioma, can distinguish this cystic lesion from Rathke's cleft cyst.
    Keywords: Braf V 600 E Mutation ; Papillary Craniopharyngioma ; Pyrosequencing ; R Athke'S Cleft Cysts ; Ve 1 Immunohistochemistry
    ISSN: 0305-1846
    E-ISSN: 1365-2990
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  • 2
    In: Nature, 2018
    Description: Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
    Keywords: DNA Methylation ; Tumors ; Standardization ; Data Processing ; Classification ; Methylation ; Brain Cancer ; Bioinformatics ; Cancer ; Generalized Linear Models ; DNA Methylation ; Diagnosis ; Tumors ; Genomes ; Classification ; Central Nervous System ; Central Nervous System ; Diagnosis ; Cancer ; Learning Algorithms ; Diagnostic Software ; Data Processing ; Tumors ; Central Nervous System ; Gene Expression ; Standardization ; Classification ; Cancer ; Classifiers ; Classification ; Clinical Trials ; Deoxyribonucleic Acid–DNA ; Probability ; Diagnostic Systems ; Nervous System ; Methylation ; Data Processing ; Tumors ; Data Processing ; Deoxyribonucleic Acid–DNA ; Deoxyribonucleic Acid–DNA ; World Health Organization;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 3
  • 4
    Language: English
    In: Annals of Hematology, 2015, Vol.94(2), pp.351-353
    Description: Byline: Maximilian Merz (1), Leonille Schweizer (2), Modar Kentar (3), Till Schneider (4), Hartmut Goldschmidt (1,5), Jens Hillengass (1) Author Affiliation: (1) Department of Hematology, University Hospital of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany (2) Department of Neuropathology, University Hospital of Heidelberg, Heidelberg, Germany (3) Department of Neurosurgery, University Hospital of Heidelberg, Heidelberg, Germany (4) Department of Neuroradiology, University Hospital of Heidelberg, Heidelberg, Germany (5) National Center for Tumor Diseases, Heidelberg, Germany Article History: Registration Date: 19/06/2014 Received Date: 10/06/2014 Accepted Date: 19/06/2014 Online Date: 29/06/2014
    Keywords: Multiple Myeloma ; Head Injuries;
    ISSN: 0939-5555
    E-ISSN: 1432-0584
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  • 5
    Language: English
    In: Acta neuropathologica communications, 14 February 2014, Vol.2, pp.19
    Description: IDH mutations frequently occur in diffuse gliomas and result in a neo-enzymatic activity that results in reduction of α-ketoglutarate to D-2-hydroxyglutarate. In gliomas, the frequency of IDH1 mutations in codon 132 increases in the order R132L-R132S-R132G-R132C-R132H with R132H constituting more than 90% of all IDH1 mutations. We determined the levels of D-2-hydroxyglutarate in glioma tissues with IDH1 mutations. D-2-hydroxyglutarate levels increased in the order of R132H-R132C-R132S/R132G/R132L. We expressed and purified IDH1 wild type and mutant protein for biochemical characterization. Enzyme kinetics of mutant IDH protein correlated well with D-2-hydroxyglutarate production in cells with R132H exhibiting the highest and R132L the lowest KM for α-ketoglutarate. Addition of D-2-hydroxyglutarate to the medium of cell lines revealed an inhibitory effect at higher concentrations. Migration of LN229 increased at lower D-2-hydroxyglutarate concentrations while higher concentrations showed no effect. These findings may suggest natural selection against the rare IDH1R132 mutations in human glioma due to toxicity caused by high levels of D-2-hydroxyglutarate.
    Keywords: Brain Neoplasms -- Genetics ; Glioma -- Genetics ; Glutarates -- Metabolism ; Isocitrate Dehydrogenase -- Genetics ; Mutation -- Genetics
    E-ISSN: 2051-5960
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  • 6
    Language: English
    In: BMC Cancer, 01 November 2018, Vol.18(1), pp.1-9
    Description: Abstract Background Rearrangements of the anaplastic lymphoma kinase (ALK) belong to the promising targets in the therapy of advanced non-small cell lung cancer (NSCLC) and are predominantly detected by immunohistochemistry (IHC) and/or fluorescence in-situ hybridization (FISH). However, both methods occasionally produce discordant results, especially in so-called borderline (BL) cases, showing ALK FISH-positive signals in 10–20% of the tumor nuclei around the cutoff (15%). This leads to a diagnostic and thus to a therapeutic dilemma. Methods We selected 18 unequivocal (12 ALK IHC/FISH-negative; 6 ALK IHC/FISH-positive) and 15 equivocal samples with discordant results between FISH (Abbott, Vysis LSI ALK Dual Color) and IHC (Ventana, D5F3), including cases with FISH-BL results, for further RNA based-analysis. To detect ALK rearrangement at the transcriptional level, RNA was analyzed using a targeted multiplex-PCR panel followed by IonTorrent sequencing and by direct transcript counting using a digital probe-based assay (NanoString). Sensitivity of both methods was defined using RNA obtained from an ALK-positive cell line dilution series. Results Cases with unequivocal IHC/FISH results showed concordant data with both RNA-based methods, whereas the three IHC-negative/FISH-positive samples were negative. The four IHC-negative/FISH-BL-negative cases, as well as the five IHC-negative/FISH-BL-positive samples showed negative results by massive parallel sequencing (MPS) and digital probe-based assay. The two IHC-positive/FISH-BL-positive cases were both positive on the RNA-level, whereas a tumor with questionable IHC and FISH-BL-positive status displayed no ALK fusion transcript. Conclusions The comparison of methods for the confirmation of ALK rearrangements revealed that the detection of ALK protein by IHC and ALK fusion transcripts on transcriptional level by MPS and the probe-based assay leads to concordant results. Only a small proportion of clearly ALK FISH-positive cases are unable to express the ALK protein and ALK fusion transcript which might explain a non-responding to ALK inhibitors. Therefore, our findings led us to conclude that ALK testing should initially be based on IHC and/or RNA-based methods.
    Keywords: Non-Small Cell Lung Cancer (Nsclc) ; Anaplastic Lymphoma Kinase (Alk) ; Fluorescence in-Situ Hybridization (FISH) ; Immunohistochemistry (Ihc) ; Massive Parallel Sequencing (MPS) ; Nanostring ; Medicine
    E-ISSN: 1471-2407
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  • 7
    Language: English
    In: Acta neuropathologica communications, 29 February 2016, Vol.4, pp.20
    Description: Craniopharyngiomas (CP) are rare epithelial tumors of the sellar region. Two subtypes, adamantinomatous (adaCP) and papillary CP (papCP), were previously identified based on histomorphological and epidemiological aspects. Recent data indicates that both variants are defined by specific genetic alterations, and influenced by distinct molecular pathways and particular origins. The fact that CP is an uncommon tumor entity renders studies on large cohorts difficult and exceptional. In order to achieve further insights distinguishing CP variants, we conducted whole genome methylation (450 k array) and microarray-based gene expression studies in addition to CTNNB1 and BRAF mutation analysis using a comprehensive cohort of 80 adaCP and 35 papCP. BRAF V600E mutations were solely found in the papCP subgroup and were not detectable in adaCP samples. In contrast, CTNNB1 mutations were exclusively detected in adaCP. The methylome fingerprints assigned DNA specimens to entity-specific groups (papCP (n = 18); adaCP (n = 25)) matching perfectly with histology-based diagnosis, suggesting that they represent truly distinct biological entities. However, we were not able to detect within the adaCP group (including 11 pediatric and 14 adult cases) a significant difference in methylation signature by age. Integrative comparison of the papCP with the adaCP group based on differential gene expression and methylation revealed a distinct upregulation of Wnt- and SHH signaling pathway genes in adaCP. AdaCP and papCP thus represent distinct tumor subtypes that harbor mutually exclusive gene mutations and methylation patterns, further reflected in differences in gene expression. This study demonstrates that DNA methylation analyses are an additional method to classify CP into subtypes, and implicates a role of epigenetic mechanisms in the genesis of the respective CP variants. Detection of tumor-specific signaling pathway activation enables the possibility of target-oriented intervention.
    Keywords: Craniopharyngioma ; Mutation -- Genetics ; Pituitary Neoplasms -- Genetics ; Proto-Oncogene Proteins B-Raf -- Genetics ; Beta Catenin -- Genetics
    E-ISSN: 2051-5960
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  • 8
    In: Histopathology, November 2014, Vol.65(5), pp.613-622
    Description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1111/his.12431/abstract Byline: Christian Koelsche, Leonille Schweizer, Marcus Renner, Arne Warth, David T W Jones, Felix Sahm, David E Reuss, David Capper, Thomas Knosel, Birte Schulz, Iver Petersen, Alexis Ulrich, Eva Kristin Renker, Burkhard Lehner, Stefan M Pfister, Peter Schirmacher, Andreas Deimling, Gunhild Mechtersheimer Keywords: amplification; fusion; liposarcoma; NAB2; solitary fibrous tumour; STAT6 Aims Nuclear relocation of STAT6 has been shown in tumours with NAB2-STAT6 fusion, and has been proposed as an ancillary marker for the diagnosis of solitary fibrous tumours (SFTs). The aim of this study was to verify the utility of STAT6 immunohistology in diagnosing SFT. Methods and results A total of 689 formalin-fixed paraffin-embedded tumours comprising 35 pleural SFTs and 654 other mesenchymal tumours were investigated for STAT6 expression using immunohistochemistry. Nine dedifferentiated liposarcomas (DDLSs) and five SFTs were also examined for the presence of NAB2-STAT6 fusion at the protein level using the proximity ligation assay (PLA), and for copy number variants (CNVs) with the Illumina Infinium Human Methylation450 array. Thirty-four of 35 SFTs showed strong nuclear STAT6 expression. Furthermore, five of 68 DDLSs, two of 130 undifferentiated pleomorphic sarcomas and one of 63 cases of nodular fasciitis showed moderate to strong nuclear STAT6 expression. The PLA indicated the presence of NAB2-STAT6 fusion protein in SFTs, but signal was also detected in some DDLSs. Copy number analysis showed an overall low frequency of chromosomal imbalances in SFTs, but complex karyotypes in DDLSs, including amplification of STAT6 and MDM2 loci. Conclusions The detection of nuclear relocation of STAT6 with immunohistochemistry is a characteristic of SFTs, and may serve as a diagnostic marker that indicates NAB2-STAT6 fusion and helps to discriminate SFTs from histological mimics. Article Note: A.v.D. and G.M. contributed equally to this work. CAPTION(S): Figure S1. Copy number plots of five solitary fibrous tumours (SFTs) and nine dedifferentiated liposarcomas (DDLSs) derived from 450k array data with chromosomal gains (green) and chromosomal losses (red). Figure S2. Histological mimic of a solitary fibrous tumour (SFT) with absence of nuclear STAT6 expression (also depicted in Figure 1B). Figure S3. Solitary fibrous tumour (SFT) with strong nuclear STAT6 expression (A) and absence of MDM2 expression (B).
    Keywords: Amplification ; Fusion ; Liposarcoma ; 2 ; Solitary Fibrous Tumour ; 6
    ISSN: 0309-0167
    E-ISSN: 1365-2559
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  • 9
    Language: English
    In: Acta Neuropathologica, 2013, Vol.125(3), pp.351-358
    Description: 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.
    Keywords: Meningioma ; Secretory ; KLF4 ; TRAF7 ; NF2 ; Krüppel-like factor 4
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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  • 10
    Language: English
    In: Acta Neuropathologica, 2013, Vol.126(5), pp.757-762
    Description: The activating E17K mutation in the AKT1 gene has been detected in several tumor entities. Currently several clinical studies with specific AKT1 inhibitors are under way. To determine whether AKT1 mutations are involved in human tumors of the nervous system, we examined a series of 1,437 tumors including 391 primary intracranial brain tumors and 1,046 tumors of the coverings of the central and peripheral nervous system. AKT1 E17K mutations were exclusively seen in meningiomas and occurred in 65 of 958 of these tumors. A strong preponderance was seen in the variant of meningothelial meningioma WHO grade I of basal and spinal localization. In contrast, AKT1 E17K mutations were rare in WHO grade II and absent in WHO grade III meningiomas. In order to more effectively detect this mutation, we tested for immunohistochemical markers associated with this alteration. We observed strong up-regulation of SFRP1 expression in all meningiomas with AKT1 E17K mutation and in HEK293 cells after transfection with mutant AKT1 E17K, but not in meningiomas and HEK293 cells lacking this mutation.
    Keywords: Meningioma ; Meningothelial ; AKT1 ; Immunohistochemistry ; SFRP1
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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