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  • 1
    In: Neuro-Oncology, 2018, Vol. 20(suppl1), pp.i16-i16
    Description: We used Next-Generation sequencing (NGS) panels to examine somatic variation in a cohort of 41 patients, 8 of which had matched primary biopsies and recurrent biopsies from subsequent tumour resection. 38/41 (92%) of the initial tumours harbour at least one variation in a gene which interacts with the RTK/Ras/PI(3)K pathway. 6/41 (15%) of initial tumours have an SNV in the IDH pathway. 27/41 (66%) of the initial biopsy samples have at least one SNV in the Wnt signalling pathway. 29/41 (71%) of initial tumours have at least one SNV in the p53 DNA damage repair pathway, and 12/41 (29%) have an SNV in the Rb cell-cycle regulation pathway. 3/41 (7%) of initial tumours have an SNV in the Nodal TGF-β signalling pathway for chromatin remodelling and pattern development, and 3/41 (7%) samples have a G-protein gene variation. Of the recurrent tissue samples, 6/8 (75%) have at least one somatic gene variation in the RTK/Ras/PI(3)K pathway, and 2/8 (25%) samples have an SNV in the IDH pathway. 3/8 (37.5%) have an SNV in the WNT signalling pathway, 4/8 (50%) have an SNV in the P53 pathway and no variation was identified in the Rb pathway. In 1/8 (12.5%) recurrent samples had an SNV in the Nodal TGF-β signalling pathway was identified, and 2/8 (25%) have a G-protein gene variation. Of the initial biopsy samples, 19/41 (46%) harboured at least one potentially actionable SNV. Of the recurrent tissue samples, 4/11 (36%) had at least one actionable SNV. Of the matched recurrent tumours, 6/8 (75%) contain SNVs that were present in the second tumour, as well as variation lost and gained. In 2/8 (25%) recurrent tumours,variation does not appear to correlate with the initial tumour. In conclusion, mutational analysis of primary and recurrent glioblastoma reveals potentially actionable SNVs including WNT pathway variation.
    ISSN: 1522-8517
    E-ISSN: 1523-5866
    Source: Oxford University Press
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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
    Language: English
    In: International journal of clinical pharmacology and therapeutics, January 2012, Vol.50(1), pp.85-6
    Keywords: Internet ; Models, Statistical ; Randomized Controlled Trials As Topic -- Methods
    ISSN: 0946-1965
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  • 4
    Language: English
    In: Int. Journal of Clinical Pharmacology and Therapeutics, 2013, Vol.51(01), pp.84-86
    ISSN: 0946-1965
    Source: CrossRef
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  • 5
    Language: English
    In: International journal of clinical pharmacology and therapeutics, January 2013, Vol.51(1), pp.84-6
    Keywords: Research Design ; Carcinoma, Non-Small-Cell Lung -- Epidemiology ; Lung Neoplasms -- Epidemiology ; Randomized Controlled Trials As Topic -- Methods
    ISSN: 0946-1965
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 6
    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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  • 7
  • 8
    Language: English
    In: Acta neuropathologica, September 2017, Vol.134(3), pp.507-516
    Description: Pediatric glioblastoma (pedGBM) is an extremely aggressive pediatric brain tumor, accounting for ~6% of all central nervous system neoplasms in children. Approximately half of pedGBM harbor recurrent somatic mutations in histone 3 variants or, infrequently, IDH1/2. The remaining subset of pedGBM is highly heterogeneous, and displays a variety of genomic and epigenetic features. In the current study, we aimed to further stratify an H3-/IDH-wild type (wt) pedGBM cohort assessed through genome-wide molecular profiling. As a result, we identified three molecular subtypes of these tumors, differing in their genomic and epigenetic signatures as well as in their clinical behavior. We designated these subtypes 'pedGBM_MYCN' (enriched for MYCN amplification), 'pedGBM_RTK1' (enriched for PDGFRA amplification) and 'pedGBM_RTK2' (enriched for EGFR amplification). These molecular subtypes were associated with significantly different outcomes, i.e. pedGBM_RTK2 tumors show a significantly longer survival time (median OS 44 months), pedGBM_MYCN display extremely poor outcomes (median OS 14 months), and pedGBM_RTK1 tumors harbor an intermediate prognosis. In addition, the various molecular subtypes of H3-/IDH-wt pedGBM were clearly distinguishable from their adult counterparts, underlining their biological distinctiveness. In conclusion, our study demonstrates significant molecular heterogeneity of H3-/IDH-wt pedGBM in terms of DNA methylation and cytogenetic alterations. The recognition of three molecular subtypes of H3-/IDH-wt pedGBM further revealed close correlations with biological parameters and clinical outcomes and may therefore, be predictive of response to standard treatment protocols, but could also be useful for stratification for novel, molecularly based therapies.
    Keywords: Brain Tumor ; Egfr ; Glioblastoma ; Mycn ; Methylation ; Pdgfra ; Pediatric ; Prognostic ; Rtk ; Subgroup ; Survival ; Mutation ; Brain Neoplasms -- Genetics ; Glioblastoma -- Genetics ; Histones -- Genetics ; Isocitrate Dehydrogenase -- Genetics
    ISSN: 00016322
    E-ISSN: 1432-0533
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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(5), pp.793-803
    Description: EGFR amplification ( EGFR amp), the combination of gain of chromosome 7 and loss of chromosome 10 (7+/10−), and TERT promoter mutation (p TERT mut) are alterations frequently observed in adult IDH -wild-type ( IDH wt) glioblastoma (GBM). In the absence of endothelial proliferation and/or necrosis, these alterations currently are considered to serve as a surrogate for upgrading IDH wt diffuse or anaplastic astrocytoma to GBM. Here, we set out to determine the distribution of EGFR amp, 7+/10−, and p TERT mut by analyzing high-resolution copy-number profiles and next-generation sequencing data of primary brain tumors. In addition, we addressed the question whether combinations of partial gains on chromosome 7 and partial losses on chromosome 10 exhibited a diagnostic and prognostic value similar to that of complete 7+/10−. Several such combinations proved relevant and were combined as the 7/10 signature. Our results demonstrate that EGFR amp and the 7/10 signature are closely associated with IDH wt GBM. In contrast, p TERT mut is less specific for IDH wt GBM. We conclude that, in the absence of endothelial proliferation and/or necrosis, the detection of EGFR amp is a very strong surrogate marker for the diagnosis of GBM in IDH wt diffuse astrocytic tumors. The 7/10 signature is also a strong surrogate marker. However, care should be taken to exclude pleomorphic xanthoastrocytoma. p TERT mut is less restricted to this entity and needs companion analysis by other molecular markers to serve as a surrogate for diagnosing IDH wt GBM. A combination of any two of EGFR amp, the 7/10 signature and p TERT mut, is highly specific for IDH wt GBM and the combination of all three alterations is frequent and exclusively seen in IDH wt GBM.
    Keywords: amplification ; Chromosome 7 gain ; Chromosome 10 loss ; 7+/10− ; 7+/10q− ; promoter mutation ; Glioblastoma ; Astrocytoma ; Pleomorphic xanthoastrocytoma
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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