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  • Schittenhelm, Jens  (34)
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  • 1
    In: Neuro-Oncology, 2014, Vol. 16(suppl5), pp.v103-v103
    Description: Astrocytoma and oligodendroglioma are histologically and genetically well-defined entities. The majority of astrocytomas harbor concurrent TP53 and ATRX mutations while most oligodendrogliomas carry the 1p/19q co-deletion. Both entities share high frequencies of IDH mutations. In contrast, oligoastrocytomas (OA) appear less clearly defined and, therefore, there is an ongoing debate whether these tumors indeed constitute an entity or whether they represent a mixed bag containing both, astrocytomas and oligodendrogliomas. We investigated 43 OA diagnosed in different institutions employing histology, immunohistochemistry and in-situ hybridization addressing the molecular genetic markers IDH1R132H, TP53, ATRX and 1p/19q loss. In all but one OA the combination of nuclear p53 accumulation and ATRX loss was mutually exclusive with 1p/19q co-deletion. In 31/43 OA only alterations typical for oligodendroglioma were observed while in 11/43 OA only indicators typical for astrocytomas were detected. A single case exhibited both, nuclear expression of p53, ATRX loss, IDH1 mutation and 1p/19q loss. However, this was the only patient undergoing radiotherapy prior to surgery, possibly resulting in acquisition of this uncommon combination. In fact, evaluation of the initial lesion demonstrated retained ATRX expression and no p53 upregulation. In OA with oligodendroglioma typical alterations, the portions corresponding to astrocytic part were determined as reactive (harbouring none of the alterations), while in OA with astrocytoma typical alterations the portions corresponding to oligodendroglial differentiation were neoplastic (harbouring identical alterations as the histologically astrocytic part). These data provide strong evidence against the existence of an independent OA entity. (under revision for Acta Neuopathologica)
    Keywords: Data Processing ; Astrocytoma ; Osteoarthritis ; Oligodendroglioma ; Radiotherapy ; Oncology ; Tumors ; P53 Protein ; Oligoastrocytoma ; Differentiation ; Classification ; Surgery ; Genetic Markers ; Mutation ; Immunohistochemistry ; Neurogenetics;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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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: 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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  • 4
    Language: English
    In: Acta Neuropathologica, 2018, Vol.136(2), pp.273-291
    Description: Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas. T-distributed stochastic neighbor-embedding (t-SNE) and hierarchical clustering analysis of these 102 cases against 158 reference cases from 12 glioma reference classes revealed that a subset of 83 of these tumors share a common DNA methylation profile that is distinct from the reference classes. These 83 tumors were thus denominated DNA methylation class anaplastic astrocytoma with piloid features (MC AAP). The 19 remaining tumors were distributed amongst the reference classes, with additional testing confirming the molecular diagnosis in most cases. Median age of patients with MC AAP was 41.5 years. The most frequent localization was the posterior fossa (74%). Deletions of CDKN2A/B (66/83, 80%), MAPK pathway gene alterations (49/65, 75%, most frequently affecting NF1 , followed by BRAF and FGFR1 ) and mutations of ATRX or loss of ATRX expression (33/74, 45%) were the most common molecular alterations. All tumors were IDH1/2 wildtype. The MGMT promoter was methylated in 38/83 tumors (45%). Outcome analysis confirmed an unfavorable clinical course in comparison to PA, but better than IDH wildtype glioblastoma. In conclusion, we show that a subset of histologically defined anaplastic pilocytic astrocytomas forms a separate DNA methylation cluster, harbors recurrent alterations in MAPK pathway genes in combination with alterations of CDKN2A/B and ATRX , affects patients who are on average older than those diagnosed with PA and has an intermediate clinical outcome.
    Keywords: Anaplastic pilocytic astrocytoma ; Pilocytic astrocytoma with anaplasia ; Methylation profile based classification ; Panel sequencing ; ATRX ; BRAF ; NF1 ; FGFR1 ; MGMT ; CDKN2A/B ; Molecular characterization ; DNA copy number alterations
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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  • 5
    In: The American Journal of Surgical Pathology, 2010, Vol.34(8), pp.1199-1204
    Description: Differentiation of gliomas and reactive gliosis may be challenging both at primary tumor occurrence and at posttherapy biopsy. The most frequent IDH1 mutation found in the majority of WHO grade II and III gliomas can be visualized with an antibody specifically detecting mutant IDH1 protein. In this study, mIDH1R132H immunoreactivity in 120 reactive gliosis specimens of various etiologies is compared with Wilms Tumor 1 (WT1) and p53 expression, both markers applied for the differentiation of reactive gliosis and glioma. Although WT1 and p53 positive glial cells were found in 17% and 63% of cases respectively, all samples were negative for mIDH1R132H. Furthermore, we investigated 19 posttherapy gliomas (6 WHO II, 13 WHO III) with extensive reactive changes and detected mIDH1R132H positive cells in 13 specimens. In 5 of these cases, tumor cells were missed by conventional staining, showing the improved sensitivity of mIDH1R132H. Thus, mIDH1R132H is a tumor-specific marker that is superior to other established markers to differentiate reactive from neoplastic cells in grade II and III gliomas and allows identifying tumor cells in posttherapy specimens with extensive reactive changes. As IDH mutations are not characteristic of grade IV primary glioblastomas, this antibody cannot differentiate primary glioblastoma from reactive gliosis. Thus, caution has to be taken and a combined panel with other markers is needed.
    Keywords: Immunohistochemistry ; Mutation ; Biomarkers, Tumor -- Analysis ; Brain Neoplasms -- Enzymology ; Glioma -- Enzymology ; Gliosis -- Diagnosis ; Isocitrate Dehydrogenase -- Analysis ; Neuroglia -- Enzymology;
    ISSN: 0147-5185
    E-ISSN: 15320979
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  • 6
    In: Journal Of The National Cancer Institute, 2016, Vol. 108(5)
    Description: The World Health Organization (WHO) classification and grading system attempts to predict the clinical course of meningiomas based on morphological parameters. However, because of high interobserver variation of some criteria, more reliable prognostic markers are required. Here, we assessed the TERT promoter for mutations in the hotspot regions C228T and C250T in meningioma samples from 252 patients. Mutations were detected in 16 samples (6.4% across the cohort, 1.7%, 5.7%, and 20.0% of WHO grade I, II, and III cases, respectively). Data were analyzed by t test, Fisher’s exact test, log-rank test, and Cox proportional hazard model. All statistical tests were two-sided. Within a mean follow-up time in surviving patients of 68.1 months, TERT promoter mutations were statistically significantly associated with shorter time to progression ( P 〈 .001). Median time to progression among mutant cases was 10.1 months compared with 179.0 months among wild-type cases. Our results indicate that the inclusion of molecular data (ie, analysis of TERT promoter status) into a histologically and genetically integrated classification and grading system for meningiomas increases prognostic power. Consequently, we propose to incorporate the assessment of TERT promoter status in upcoming grading schemes for meningioma.
    Keywords: Meningioma – Genetic Aspects ; Recurrence (Disease) – Genetic Aspects;
    ISSN: 0027-8874
    E-ISSN: 1460-2105
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  • 7
    Language: English
    In: Acta Neuropathologica, 2011, Vol.121(2), pp.241-252
    Description: Isocitrate dehydrogenase 1 ( IDH1 ) mutations are frequent in astrocytomas, oligoastrocytomas and oligodendrogliomas. We previously reported the generation of a mutation-specific antibody that specifically detects R132H mutated IDH1 protein (clone H09). Here, we investigate the feasibility of H09 immunohistochemistry to differentiate between oligodendrogliomas/oligoastrocytomas and other tumors with similar morphology. A total of 274 brain tumors presenting with focal or extensive clear cell morphology were investigated. High numbers of H09-positive cases were observed in adult grade II oligodendrogliomas (67 of 74, 91%), grade III oligodendrogliomas (65 of 69, 94%), grade II oligoastrocytomas (11 of 14, 79%) and grade III oligoastrocytomas (10 of 11, 91%). All cases of pediatric oligodendrogliomas ( n  = 7), neurocytomas ( n  = 41, 35 central, 4 extraventricular, 2 cerebellar liponeurocytomas), dysembryoplastic neuroepithelial tumors ( n  = 21), clear cell ependymomas ( n  = 8), clear cell meningiomas ( n  = 9) as well as 12 primary glioblastomas with oligodendroglial differentiation and 5 pilocytic astrocytomas with oligodendroglial-like differentiation were negative for H09 immunohistochemistry. Three oligodendrogliomas with neurocytic differentiation had evidence of IDH1 / IDH2 mutations either by H09 immunohistochemistry or direct sequencing. We conclude that in tumors with an oligodendroglioma-like morphology, binding of H09 is highly specific for oligodendrogliomas or oligoastrocytomas and substantially helps in the discrimination from other clear cell tumors. Negative H09 immunohistochemistry of an adult oligodendroglioma or oligoastrocytoma should prompt the consideration of other clear cell neoplasms. Further, our observations firmly assign oligodendrogliomas with neurocytic differentiation to the group of oligodendrogliomas and demonstrate that H09 is especially helpful for the difficult discrimination of such lesions from extraventricular neurocytomas.
    Keywords: Isocitrate dehydrogenase ; IDH1 ; R132H ; Antibody ; Oligodendroglioma ; Clear cell
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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  • 8
    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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  • 9
    In: Neuro-Oncology, 2018, Vol. 20(suppl2), pp.i108-i108
    Description: Diffuse leptomeningeal glioneuronal tumors (DLGNT) represent a rare CNS neoplasm included in the latest WHO classification update from 2016. The wide spectrum of histological and radiological features can make this enigmatic tumor entity difficult to diagnose. In recent years, large-scale genomic and epigenomic analyses have provided insight into key genetic alterations in pediatric brain tumors. Through genome-wide DNA methylation screening of 〉25,000 tumors, we discovered a distinct class comprising 31 tumors, mostly diagnosed as DLGNTs. Copy number profiles derived from the methylation arrays revealed unifying characteristics, including loss of chromosomal arm 1p in 100% of cases. Furthermore, this molecular DLGNT class could be subdivided into two subgroups (DLGNT-pediatric and DLGNT-adult), with all DLGNT-adult additionally displaying gain of chromosomal arm 1q. Co-deletion of 1p/19q was frequently observed in both subgroups, especially in DLGNT-pediatric cases. Both subgroups also displayed recurrent genetic alterations leading to an aberrant MAPK/ERK pathway, with KIAA1549:BRAF fusion being the most frequent event. Other alterations included fusions of NTRK1/2/3 and TRIM33:RAF1. Age at diagnosis was significantly lower (median 5 vs 14 years, p〈0.005) and clinical course less aggressive, in the DLGNT-pediatric group (5-yr OS 100%, vs 50% in DLGNT-adult). Our study proposes an additional molecular layer to the current histopathological classification of DLGNT, of particular use for cases not displaying typical morphological or radiological characteristics. Recurrent 1p deletion and MAPK/ERK pathway activation represent diagnostic and therapeutic biomarkers, laying the foundation for future clinical trials with e.g. MEK inhibitors that may improve the clinical outcome of patients with DLGNT.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 10
    Language: English
    In: Acta Neuropathologica, 2014, Vol.128(4), pp.551-559
    Description: Astrocytoma and oligodendroglioma are histologically and genetically well-defined entities. The majority of astrocytomas harbor concurrent TP53 and ATRX mutations, while most oligodendrogliomas carry the 1p/19q co-deletion. Both entities share high frequencies of IDH mutations. In contrast, oligoastrocytomas (OA) appear less clearly defined and, therefore, there is an ongoing debate whether these tumors indeed constitute an entity or whether they represent a mixed bag containing both astrocytomas and oligodendrogliomas. We investigated 43 OA diagnosed in different institutions employing histology, immunohistochemistry and in situ hybridization addressing surrogates for the molecular genetic markers IDH1 R132H, TP53 , ATRX and 1p/19q loss. In all but one OA the combination of nuclear p53 accumulation and ATRX loss was mutually exclusive with 1p/19q co-deletion. In 31/43 OA, only alterations typical for oligodendroglioma were observed, while in 11/43 OA, only indicators for mutations typical for astrocytomas were detected. A single case exhibited a distinct pattern, nuclear expression of p53, ATRX loss, IDH1 mutation and partial 1p/19q loss. However, this was the only patient undergoing radiotherapy prior to surgery, possibly contributing to the acquisition of this uncommon combination. In OA with oligodendroglioma typical alterations, the portions corresponding to astrocytic part were determined as reactive, while in OA with astrocytoma typical alterations the portions corresponding to oligodendroglial differentiation were neoplastic. These data provide strong evidence against the existence of an independent OA entity.
    Keywords: Mixed glioma ; Oligoastrocytoma ; 1p/19q ; ATRX ; TP53 ; IDH1
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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