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  • Korshunov, Andrey  (50)
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  • 1
    In: Neuro-Oncology, 2018, Vol. 20(suppl2), pp.i182-i182
    Description: Precise diagnosis and robust detection of actionable alterations is required for individualized treatments. The Pediatric Targeted Therapy (PTT) 2.0 program aims at improvement of diagnostic accuracy and detection of targetable alterations by extended molecular diagnostics. The impact of these analyses on clinical management is being evaluated. Pediatric patients with relapsed or progressive tumors after treatment according to standard protocols are included, independent of the histological diagnosis. Formalin fixed paraffin embedded material and a blood sample for germline correction are requested. The methods employed are DNA methylation array, customized targeted gene panel sequencing (130 genes), RNA and Sanger sequencing in selected cases, and immunohistochemistry (IHC) of selected markers. A questionnaire-based follow-up is used to determine the clinical impact of the analysis. We have included n=111 cases from 22.02.2017.-31.12.2017, analysis was completed for n=83 cases (75%) at the time of abstract submission. The most common entities were brain tumors (n=56/83, 67%). DNA methylation array alone allowed diagnostic classification in n=45/83 cases (54.2%) and n=34/56 brain tumor cases (60,7%), respectively. Actionable targets as detected by copy number calculation, gene panel sequencing, RNA sequencing and IHC were found in n=47/83 cases (56.6%). Pathogenic germline alterations with clinical relevance were identified in n=7/83 cases (8.4%) and were confirmed by Sanger sequencing. Follow-up analyses are ongoing. In conclusion, combination of next-generation diagnostics such as methylation arrays and targeted sequencing in addition to selected IHC markers added robust information concerning diagnosis and targetable alterations. The impact on clinical decision-making and on outcome is currently being evaluated.
    Keywords: Medicine;
    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
    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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  • 4
    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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  • 5
    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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  • 6
    Language: English
    In: Acta Neuropathologica, 2018, Vol.136(2), pp.327-337
    Description: Patients with DICER1 predisposition syndrome have an increased risk to develop pleuropulmonary blastoma, cystic nephroma, embryonal rhabdomyosarcoma, and several other rare tumor entities. In this study, we identified 22 primary intracranial sarcomas, including 18 in pediatric patients, with a distinct methylation signature detected by array-based DNA-methylation profiling. In addition, two uterine rhabdomyosarcomas sharing identical features were identified. Gene panel sequencing of the 22 intracranial sarcomas revealed the almost unifying feature of DICER1 hotspot mutations (21/22; 95%) and a high frequency of co-occurring TP53 mutations (12/22; 55%). In addition, 17/22 (77%) sarcomas exhibited alterations in the mitogen-activated protein kinase pathway, most frequently affecting the mutational hotspots of KRAS (8/22; 36%) and mutations or deletions of NF1 (7/22; 32%), followed by mutations of FGFR4 (2/22; 9%), NRAS (2/22; 9%), and amplification of EGFR (1/22; 5%). A germline DICER1 mutation was detected in two of five cases with constitutional DNA available. Notably, none of the patients showed evidence of a cancer-related syndrome at the time of diagnosis. In contrast to the genetic findings, the morphological features of these tumors were less distinctive, although rhabdomyoblasts or rhabdomyoblast-like cells could retrospectively be detected in all cases. The identified combination of genetic events indicates a relationship between the intracranial tumors analyzed and DICER1 predisposition syndrome-associated sarcomas such as embryonal rhabdomyosarcoma or the recently described group of anaplastic sarcomas of the kidney. However, the intracranial tumors in our series were initially interpreted to represent various tumor types, but rhabdomyosarcoma was not among the typical differential diagnoses considered. Given the rarity of intracranial sarcomas, this molecularly clearly defined group comprises a considerable fraction thereof. We therefore propose the designation “spindle cell sarcoma with rhabdomyosarcoma-like features, DICER1 mutant” for this intriguing group.
    Keywords: DICER1 ; TP53 ; MAPK ; CNS ; Sarcoma ; NGS ; DNA-methylation profiling ; EPIC array
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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  • 7
    Language: English
    In: Acta Neuropathologica, 2018, Vol.136(2), pp.303-313
    Description: Medulloblastoma with extensive nodularity (MBEN) is a rare histological variant of medulloblastoma (MB). These tumors are usually occurring in the first 3 years of life and are associated with good prognosis. Molecular analyses of MBEN, mostly limited to single cases or small series, have shown that they always classify as sonic hedgehog (SHH)-driven MB. Here, we have analyzed 25 MBEN through genome-wide DNA methylation, copy-number profiling and targeted next-generation sequencing. Results of these analyses were compared with molecular profiles of other SHH MB histological variants. As expected, the vast majority of MBEN (23/25) disclosed SHH-associated epigenetic signatures and mutational landscapes but, surprisingly, two MBEN were classified as Group 3/4 MB. Most MBEN classified as SHH MB displayed SHH-related and mutually exclusive mutations in either SUFU, or PTCH1 , or SMO at similar frequencies. However, only SUFU mutations were also identified in the germ-line. Most of SUFU -associated MBEN eventually recurred but patients were treated successfully with second-line high-dose chemotherapy. Altogether, our data show that risk stratification even for well-recognizable histologies such as MBEN cannot rely on histology alone but should include additional molecular analyses such as methylation profiling and DNA sequencing. For all patients with “MBEN” histology, we recommend sequencing SUFU and PTCH1 in the tumor as well as in the germ-line for further clinical stratification and choice of the optimal treatment strategy upfront.
    Keywords: Medulloblastoma ; MBEN ; SHH MB ; SUFU
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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  • 8
    Language: English
    In: Acta Neuropathologica, 2018, Vol.136(2), pp.181-210
    Description: Recently, we described a machine learning approach for classification of central nervous system tumors based on the analysis of genome-wide DNA methylation patterns [6]. Here, we report on DNA methylation-based central nervous system (CNS) tumor diagnostics conducted in our institution between the years 2015 and 2018. In this period, more than 1000 tumors from the neurosurgical departments in Heidelberg and Mannheim and more than 1000 tumors referred from external institutions were subjected to DNA methylation analysis for diagnostic purposes. We describe our current approach to the integrated diagnosis of CNS tumors with a focus on constellations with conflicts between morphological and molecular genetic findings. We further describe the benefit of integrating DNA copy-number alterations into diagnostic considerations and provide a catalog of copy-number changes for individual DNA methylation classes. We also point to several pitfalls accompanying the diagnostic implementation of DNA methylation profiling and give practical suggestions for recurring diagnostic scenarios.
    Keywords: DNA methylation ; EPIC array ; Tumor classification ; Copy-number variation
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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  • 9
    Language: English
    In: Acta Neuropathologica, 2017, Vol.133(2), pp.325-327
    Keywords: Astrocytoma -- Genetics ; Brain Neoplasms -- Genetics ; Cyclin D2 -- Genetics;
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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  • 10
    Language: English
    In: Acta Neuropathologica, 2015, Vol.129(6), pp.867-873
    Description: The WHO 2007 classification of tumors of the CNS distinguishes between diffuse astrocytoma WHO grade II (A II WHO2007 ) and anaplastic astrocytoma WHO grade III (AA III WHO2007 ). Patients with A II WHO2007 are significantly younger and survive significantly longer than those with AA III WHO2007 . So far, classification and grading relies on morphological grounds only and does not yet take into account IDH status, a molecular marker of prognostic relevance. We here demonstrate that WHO 2007 grading performs poorly in predicting prognosis when applied to astrocytoma carrying IDH mutations. Three independent series including a total of 1360 adult diffuse astrocytic gliomas with IDH mutation containing 683 A II IDHmut , 562 AA III IDHmut and 115 GBM IDHmut have been examined for age distribution and survival. In all three series patients with A II IDHmut and AA III IDHmut were of identical age at presentation of disease (36–37 years) and the difference in survival between grades was much less (10.9 years for A II IDHmut , 9.3 years for AA III IDHmut ) than that reported for A II WHO2007 versus AA III WHO2007 . Our analyses imply that the differences in age and survival between A II WHO2007 and AA III WHO2007 predominantly depend on the fraction of IDH -non-mutant astrocytomas in the cohort. This data poses a substantial challenge for the current practice of astrocytoma grading and risk stratification and is likely to have far-reaching consequences on the management of patients with IDH -mutant astrocytoma.
    Keywords: Brain Tumors ; Central Nervous System ; Age Composition ; Age ; Data Processing ; Classification ; Astrocytoma ; Prognosis ; Survival ; Glioma ; Tumors ; Mutation ; Neurology & Neuropathology;
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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