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  • Capper, David  (81)
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  • 1
    Language: English
    In: Oncotarget, September 2012, Vol.3(9), pp.907-8
    Description: Mutation specific antibodies demonstrate the benefit of merging molecular findings with traditional diagnostic expertise. Whether this approach is of sustainable benefit has to be seen. Convincing data on colon carcinoma will be demonstrated at ESMO 2012 with the conclusion to screen patients for BRAFV600E for enrolment in an upcoming clinical trial combining BRAF and EGFR inhibitors.
    Keywords: Antibodies, Monoclonal -- Genetics ; Neoplasms -- Drug Therapy ; Proto-Oncogene Proteins B-Raf -- Genetics
    E-ISSN: 1949-2553
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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: Archives of neurology, April 2012, Vol.69(4), pp.523-6
    Description: To analyze infiltration patterns of IDH1 mutant diffuse gliomas into the brain by identification of single tumor cells applying an antibody specific to mutant IDH1 R132H protein. Immunohistochemical analysis. University hospital. Whole-brain and hemisphere sections of 4 patients diagnosed with diffuse glioma. Tumor cells were identified in areas that appeared inconspicuous macroscopically and at histological analysis with respect to cellularity, cellular pleomorphism, or mitotic activity in all cases. Detection of single tumor cells throughout the brain demonstrates diffuse glioma to represent systemic brain disease.
    Keywords: Brain Neoplasms -- Genetics ; Glioma -- Genetics ; Isocitrate Dehydrogenase -- Genetics ; Mutation -- Genetics
    ISSN: 00039942
    E-ISSN: 1538-3687
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  • 4
    Language: English
    In: The Journal of clinical investigation, February 2015, Vol.125(2), pp.593-606
    Description: For a targeted cancer vaccine to be effective, the antigen of interest needs to be naturally processed and presented on MHC by the target cell or an antigen-presenting cell (APC) in the tumor stroma. The presence of these characteristics is often assumed based on animal models, evaluation of antigen-overexpressing APCs in vitro, or assays of material-consuming immune precipitation from fresh solid tissue. Here, we evaluated the use of an alternative approach that uses the proximity ligation assay (PLA) to identify the presentation of an MHC class II-restricted antigen in paraffin-embedded tissue sections from patients with brain tumors. This approach required a specific antibody directed against the epitope that was presented. We used an antibody that specifically binds an epitope of mutated isocitrate dehydrogenase type 1 (IDH1R132H), which is frequently expressed in gliomas and other types of tumors. In situ PLA showed that the IDH1R132H epitope colocalizes with MHC class II in IDH1R132H-mutated glioma tissue. Moreover, PLA demonstrated colocalization between the class II epitope-containing melanoma antigen New York esophageal 1 and MHC class II. Collectively, our data suggest that PLA may be a useful tool to acquire information on whether an antigen is presented in situ, and this technique has potential to guide clinical studies that use antigen-specific cancer immunotherapy.
    Keywords: Antigen Presentation ; Mutation, Missense ; Antigen-Presenting Cells -- Immunology ; Brain Neoplasms -- Immunology ; Glioma -- Immunology ; Immunohistochemistry -- Methods ; Isocitrate Dehydrogenase -- Immunology
    ISSN: 00219738
    E-ISSN: 1558-8238
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  • 5
    Language: English
    In: Acta Neuropathologica, 2011, Vol.122(1), pp.11-19
    Description: Activating mutations of the serine threonine kinase v-RAF murine sarcoma viral oncogene homolog B1 (BRAF) are frequent in benign and malignant human tumors and are emerging as an important biomarker. Over 95% of BRAF mutations are of the V600E type and specific small molecular inhibitors are currently under pre-clinical or clinical investigation. BRAF mutation status is determined by DNA-based methods, most commonly by sequencing. Here we describe the development of a monoclonal BRAF V600E mutation-specific antibody that can differentiate BRAF V600E and wild type protein in routinely processed formalin-fixed and paraffin-embedded tissue. A total of 47 intracerebral melanoma metastases and 21 primary papillary thyroid carcinomas were evaluated by direct sequencing of BRAF and by immunohistochemistry using the BRAF V600E mutation-specific antibody clone VE1. Correlation of VE1 immunohistochemistry and BRAF sequencing revealed a perfect match for both papillary thyroid carcinomas and melanoma metastases. The staining intensity in BRAF V600E mutated tumor samples ranged from weak to strong. The generally homogenous VE1 staining patterns argue against a clonal heterogeneity of the tumors investigated. Caution is essential when only poorly preserved tissue is available for VE1 immunohistochemical analysis or when tissues with only little total BRAF protein are analyzed. Immunohistochemistry using antibody VE1 may substantially facilitate molecular analysis of BRAF V600E status for diagnostic, prognostic, and predictive purposes.
    Keywords: BRAF ; V600E ; Mutation ; Monoclonal antibody ; Immunohistochemistry ; Melanoma ; Papillary thyroid carcinoma ; Biomarker
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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  • 6
    Language: English
    In: Cancer Research, 10/01/2018, Vol.78(19 Supplement), pp.IA11-IA11
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 7
    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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  • 8
    In: Genes, Chromosomes and Cancer, May 2016, Vol.55(5), pp.418-427
    Description: Intraocular medulloepithelioma (IO‐MEPL) is an uncommon embryonal neuroepithelial neoplasm of the eye. Little is known about the cytogenetics, molecular biology, and pathogenesis of this tumor. In the present study we investigated the mutational landscape of 19 IO‐MEPL using targeted next‐generation sequencing. Routinely prepared paraffin‐embedded samples were assessed with high‐coverage genome sequencing on the Illumina NextSeq 500 platform using a customized gene panel set covering the coding region of 130 genes. This revealed several notable genomic alterations, including mutations of (6 tumors) and (also known as ; 5 tumors)—which are frequently recurrent and mutually exclusive molecular events for IO‐MEPL. Non‐recurrent mutations in the cancer‐associated genes , and were also identified. IO‐MEPL samples harboring a mutation disclosed few chromosomal alterations and formed a separate DNA methylation cluster, indicating potential differences in genetic and epigenetic events arising perhaps from the presence of this aberration in the tumor genome. The high proportion of recurrent somatic and mutations in this series of sporadic IO‐MEPL points to their likely important roles in the molecular pathogenesis of these rare embryonal tumors, and perhaps suggests the existence of distinct molecular variants of IO‐MEPL. Although the precise role of these recurrent mutations in the development of IO‐MEPL, and their relationship to pro‐oncogenic molecular mechanisms, have yet to be determined, unraveling their roles could eventually be exploited for nonsurgical therapies of these neoplasms. © 2016 Wiley Periodicals, Inc.
    Keywords: Tumors – Genetic Aspects;
    ISSN: 1045-2257
    E-ISSN: 1098-2264
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  • 9
    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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  • 10
    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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