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  • 1
    Language: English
    In: Molecular Immunology, 2009, Vol.46(13), pp.2474-2480
    Description: Suppressor of cytokine signaling 1 (SOCS1) belongs to a family of genes involved in inducible feedback inhibition of janus kinases (JAKs) and signal transducers and activators of transcription (STATs) signaling pathway. Recently, we were able to show that SOCS1 surprisingly translocates to the nucleus due to the presence of a functional nuclear localization signal (NLS). However, the precise nature of the NLS remained ill-defined. Here we investigated further details of the SOCS1 NLS and analyzed its functional importance. We show that nuclear transport of SOCS1 particularly depends on the second cluster of basic amino acid residues within the NLS. Neither the first nor a nearby identified third cluster of basic amino acids were sufficient for mediating nuclear localization of SOCS1. Altering the subcellular localization of SOCS1 by mutating clusters of arginine residues within the NLS did not affect the inhibition of interferon mediated STAT1 tyrosine-phosphorylation, but surprisingly led to impaired inhibitory activity of STAT mediated reporter gene induction and IFN-γ induced CD54 regulation. A SOCS-box deletion mutant (E176X) also had reduced inhibitory activity. In contrast, nuclear factor κB (NFκB) signaling was not affected by SOCS1 wt or mutants. Thus, SOCS1 may accomplish its inhibitory function in the IFN-pathway in part through nuclear localization.
    Keywords: Signal Transduction ; Cytokine Receptors ; Suppressors of Cytokine Signaling ; Subcellular Localization ; Medicine ; Biology ; Chemistry
    ISSN: 0161-5890
    E-ISSN: 1872-9142
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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 ; Central Nervous System Neoplasms -- Diagnosis;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 3
    Language: English
    In: Cell, 25 February 2016, Vol.164(5), pp.1060-1072
    Description: Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated “CNS neuroblastoma with activation (CNS NB- ),” “CNS Ewing sarcoma family tumor with alteration (CNS EFT- ),” “CNS high-grade neuroepithelial tumor with alteration (CNS HGNET- ),” and “CNS high-grade neuroepithelial tumor with alteration (CNS HGNET- ),” will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors. Highly malignant primitive neuroectodermal tumors of the CNS (CNS-PNETs) have been challenging to diagnose and distinguish from other kinds of brain tumors, but molecular profiling now reveals that these cancers can be readily classified into some known tumor types and four new entities with distinct histopathological and clinical features, paving the way for meaningful clinical trials.
    Keywords: Biology
    ISSN: 0092-8674
    E-ISSN: 1097-4172
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  • 4
    In: Brain Pathology, April 2014, Vol.24(3), pp.221-229
    Description: V600E mutation and homozygous deletion of (16) are frequent molecular alterations in pleomorphic xanthoastrocytomas (s). We investigated 49 for clinical, histological and immunohistochemical characteristics related to mutation status. mutation was detected by immunohistochemical assay and DNA sequencing in 38/49 (78%) tumors. All but one located in the temporal lobe harbored a V600E mutation (23/24; 96%) compared with 10/19 nontemporal (53%;  = 0.0009). Histological and immunohistochemical analysis demonstrated increased reticulin deposition (76% vs. 27%;  = 0.003) and a more frequent expression of 34 in ‐mutant (76% vs. 27%;  = 0.003). We further investigated the utility of combined V600E (1) and 16 analysis by immunohistochemistry to distinguish from relevant histological mimics like giant‐cell glioblastoma. Among , 38/49 (78%) were 1‐positive, and 30/49 (61%) had a loss of p16 expression. The combined features (1 positivity/16 loss) were observed in 25/49 (51%) but were not observed in giant‐cell glioblastoma (1 0/28, 16 loss 14/28). We demonstrate that temporal location, reticulin deposition and 34 expression are associated with mutation in . Combined 1 positivity and 16 loss represents a frequent immunoprofile of and may therefore constitute an additional diagnostic tool for its differential diagnosis.
    Keywords: Brain Tumor ; Braf V600e ; Cdkn2a ; 34 ; Immunohistochemistry ; Pleomorphic Xanthoastrocytoma ; 16 ; 1
    ISSN: 1015-6305
    E-ISSN: 1750-3639
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  • 5
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 15 September 2018, Vol.24(18), pp.4494-4504
    Description: In the central nervous system, distinguishing primary leptomeningeal melanocytic tumors from melanoma metastases and predicting their biological behavior solely using histopathologic criteria may be challenging. We aimed to assess the diagnostic and prognostic value of integrated molecular analysis....
    Keywords: Central Nervous System Neoplasms -- Genetics ; Melanoma -- Genetics ; Skin Neoplasms -- Genetics ; Uveal Neoplasms -- Genetics
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 6
    In: Histopathology, April 2016, Vol.68(5), pp.738-745
    Description: Byline: Christian Koelsche, Marcus Renner, Pascal Johann, Irina Leiss, Felix Sahm, Simon Schimmack, Eva Wardelmann, Eva-Kristin Renker, Peter Schirmacher, Andrey Korshunov, Andreas Deimling, Gunhild Mechtersheimer Keywords: ALT ; ATRX ; immunohistochemistry; sarcomas; telomeres Aim Nuclear [alpha]-thalassemia/mental retardation X-linked (ATRX) loss and alternative lengthening of telomeres (ALT) are linked in distinct malignancies. We therefore aimed to determine the nuclear ATRX expression correlated with ALT in a comprehensive series of sarcomas. Methods and results A total of 573 formalin-fixed paraffin-embedded sarcomas comprising 28 entities were investigated for nuclear ATRX expression by immunohistochemistry. Telomere-specific fluorescence in-situ hybridization (FISH) was used to determine the ALT phenotype in 50 sarcomas with complete or heterogeneous ATRX loss. Complete nuclear ATRX loss was detected in 58 of 573 sarcomas, all high-grade, with the highest prevalence in undifferentiated pleomorphic sarcomas (38%) and pleomorphic liposarcomas (38%), followed by dedifferentiated liposarcomas (24%), osteosarcomas (21%), leiomyosarcomas (17%), myxofibrosarcomas (11%) and malignant peripheral nerve sheath tumours (4%). Interestingly, a further 20 sarcomas, all belonging to the aforementioned entities with complete ATRX loss, presented with a heterogeneous ATRX expression pattern. ALT was observed in 41 of 42 sarcomas with complete ATRX loss, but only in two of eight sarcomas with heterogeneous expression. Conclusion Nuclear ATRX loss, either complete or heterogeneous, is encountered in a considerable number of high-grade sarcomas with non-specific genetic alterations. A causal relationship with ALT might be indicated at least in cases with a complete nuclear ATRX loss. CAPTION(S): Table S1. ATRX Primer Sequences.
    Keywords: Alt ; Atrx ; Immunohistochemistry ; Sarcomas ; Telomeres
    ISSN: 0309-0167
    E-ISSN: 1365-2559
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  • 7
    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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  • 8
    In: Brain Pathology, March 2015, Vol.25(2), pp.202-208
    Description: Melanotic tumors of the nervous system show overlapping histological characteristics but differ substantially in their biological behavior. In order to achieve a better delineation of such tumors, we performed an in‐depth molecular characterization. Eighteen melanocytomas, 12 melanomas, and 14 melanotic and 14 conventional schwannomas (control group) were investigated for methylome patterns (450k array), gene mutations associated with melanotic tumors and copy number variants (s). The methylome fingerprints assigned tumors to entity‐specific groups. Methylation groups also showed a substantial overlap with histology‐based diagnosis suggesting that they represent true biological entities. On the molecular level, melanotic schwannomas were characterized by a complex karyotype with recurrent monosomy of chromosome 22q and variable whole chromosomal gains and recurrent losses commonly involving chromosomes 1, 17p and 21. Melanocytomas carried mutations and presented with involving chromosomes 3 and 6. Melanomas were frequently mutated in the promoter, harbored additional oncogene mutations and showed recurrent chromosomal losses involving chromosomes 9, 10 and 6q, as well as gains of 22q. Together, melanotic nervous system tumors have several distinct mutational and chromosomal alterations and can reliably be distinguished by methylome profiling.
    Keywords: 450k ; Copy Number Variants ; Gna 11 ; Gnaq ; Melanocytoma ; Melanoma ; Melanotic Schwannoma ; Tert Promoter
    ISSN: 1015-6305
    E-ISSN: 1750-3639
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  • 9
    Language: English
    In: Acta Neuropathologica, 2018, Vol.136(2), pp.255-271
    Description: Olfactory neuroblastoma/esthesioneuroblastoma (ONB) is an uncommon neuroectodermal neoplasm thought to arise from the olfactory epithelium. Little is known about its molecular pathogenesis. For this study, a retrospective cohort of n  = 66 tumor samples with the institutional diagnosis of ONB was analyzed by immunohistochemistry, genome-wide DNA methylation profiling, copy number analysis, and in a subset, next-generation panel sequencing of 560 tumor-associated genes. DNA methylation profiles were compared to those of relevant differential diagnoses of ONB. Unsupervised hierarchical clustering analysis of DNA methylation data revealed four subgroups among institutionally diagnosed ONB. The largest group ( n  = 42, 64%, Core ONB) presented with classical ONB histology and no overlap with other classes upon methylation profiling-based t-distributed stochastic neighbor embedding (t-SNE) analysis. A second DNA methylation group ( n  = 7, 11%) with CpG island methylator phenotype (CIMP) consisted of cases with strong expression of cytokeratin, no or scarce chromogranin A expression and IDH2 hotspot mutation in all cases. T-SNE analysis clustered these cases together with sinonasal carcinoma with IDH2 mutation. Four cases (6%) formed a small group characterized by an overall high level of DNA methylation, but without CIMP. The fourth group consisted of 13 cases that had heterogeneous DNA methylation profiles and strong cytokeratin expression in most cases. In t-SNE analysis, these cases mostly grouped among sinonasal adenocarcinoma, squamous cell carcinoma, and undifferentiated carcinoma. Copy number analysis indicated highly recurrent chromosomal changes among Core ONB with a high frequency of combined loss of chromosome 1–4, 8–10, and 12. NGS sequencing did not reveal highly recurrent mutations in ONB, with the only recurrently mutated genes being TP53 and DNMT3A . In conclusion, we demonstrate that institutionally diagnosed ONB are a heterogeneous group of tumors. Expression of cytokeratin, chromogranin A, the mutational status of IDH2 as well as DNA methylation patterns may greatly aid in the precise classification of ONB.
    Keywords: Medicine & Public Health ; Pathology ; Neurosciences ; Medicine;
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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  • 10
    Language: English
    In: Acta Neuropathologica, 2018, Vol.136(1), pp.153-166
    Description: According to the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO), IDH-mutant astrocytic gliomas comprised WHO grade II diffuse astrocytoma, IDH-mutant (AII IDHmut ), WHO grade III anaplastic astrocytoma, IDH-mutant (AAIII IDHmut ), and WHO grade IV glioblastoma, IDH-mutant (GBM IDHmut ). Notably, IDH gene status has been made the major criterion for classification while the manner of grading has remained unchanged: it is based on histological criteria that arose from studies which antedated knowledge of the importance of IDH status in diffuse astrocytic tumor prognostic assessment. Several studies have now demonstrated that the anticipated differences in survival between the newly defined AII IDHmut and AAIII IDHmut have lost their significance. In contrast, GBM IDHmut still exhibits a significantly worse outcome than its lower grade IDH-mutant counterparts. To address the problem of establishing prognostically significant grading for IDH-mutant astrocytic gliomas in the IDH era, we undertook a comprehensive study that included assessment of histological and genetic approaches to prognosis in these tumors. A discovery cohort of 211 IDH-mutant astrocytic gliomas with an extended observation was subjected to histological review, image analysis, and DNA methylation studies. Tumor group-specific methylation profiles and copy number variation (CNV) profiles were established for all gliomas. Algorithms for automated CNV analysis were developed. All tumors exhibiting 1p/19q codeletion were excluded from the series. We developed algorithms for grading, based on molecular, morphological and clinical data. Performance of these algorithms was compared with that of WHO grading. Three independent cohorts of 108, 154 and 224 IDH-mutant astrocytic gliomas were used to validate this approach. In the discovery cohort several molecular and clinical parameters were of prognostic relevance. Most relevant for overall survival (OS) was CDKN2A/B homozygous deletion. Other parameters with major influence were necrosis and the total number of CNV. Proliferation as assessed by mitotic count, which is a key parameter in 2016 CNS WHO grading, was of only minor influence. Employing the parameters most relevant for OS in our discovery set, we developed two models for grading these tumors. These models performed significantly better than WHO grading in both the discovery and the validation sets. Our novel algorithms for grading IDH-mutant astrocytic gliomas overcome the challenges caused by introduction of IDH status into the WHO classification of diffuse astrocytic tumors. We propose that these revised approaches be used for grading of these tumors and incorporated into future WHO criteria.
    Keywords: Astrocytoma ; Glioblastoma ; IDH ; Grading ; CDKN2A/B
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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