scholarly journals Array-based DNA methylation profiling of primary lymphomas of the central nervous system

BMC Cancer ◽  
2009 ◽  
Vol 9 (1) ◽  
Author(s):  
Julia Richter ◽  
Ole Ammerpohl ◽  
José I Martín-Subero ◽  
Manuel Montesinos-Rongen ◽  
Marina Bibikova ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Central Nervous System ◽  
Nervous System ◽  
Dna Methylation Profiling ◽  
The Central Nervous System ◽  
Methylation Profiling

scholarly journals PATH-21. CLINICAL UTILITY OF DNA METHYLATION PROFILING FOR DIAGNOSIS OF CHALLENGING CENTRAL NERVOUS SYSTEM TUMORS: THE TORONTO EXPERIENCE

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi147-vi147
Author(s):  
Shirin Karimi ◽  
Jeffrey Zuccato ◽  
Yasin Mamatjan ◽  
Sheila Mansouri ◽  
Suganth Suppiah ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Central Nervous System ◽  
Nervous System ◽  
Clinical Utility ◽  
Cns Tumors ◽  
Cns Tumor ◽  
Dna Methylation Profiling ◽  
Diffuse Gliomas ◽  
Methylation Profiling

Abstract The update on the WHO classification of central nervous system (CNS) tumors incorporated molecular signatures for a more accurate diagnosis. Recently, DKFZ has demonstrated the utility of DNA methylation profiling(MP) for molecular classification of CNS tumors. We performed a prospective clinical study over the last three years to evaluate the clinical utility ofDNA MP on FFPE samples of 66 challenging CNS tumor cases using online DKFZ classifier. Eleven samples were excluded due to low tumor DNA content or low calibration(predictive) scores(CS)< 0.3.DNA MP confirmed the original pathology diagnoses in 15(27%)cases. The integrated molecular diagnoses were changed in 38/55(70%) including establishment of a new diagnostic entity, change in molecular signature and subtyping. TheWHO grades were changed in 16(27%) of the tumors; about two-thirds resulted in upgrading. We detected non-canonical IDH mutations in 9 diffuse gliomas and the CNV plots revealed false positive FISH results for 1p/19q co-deletion in two diffuse gliomas. The CNV plots contributed to the final diagnosis in 40(72%) patients. The molecular subtypes of medulloblastoma, ependymoma and glioblastoma subclasses were determined in 36(65%) cases. Seventy-five percent of cases with confirmation of initial diagnosis or change in molecular diagnosis had CS > 0.5, among which 51% had a CS >0.9. The median and range CS of cases with new diagnostic entity and confirmed cases were 0.86(0.37–0.99) and 0.98(0.42–0.99), respectably. Furthermore, we detected higher CS in IDH-mutant gliomas in comparison to glioblastoma IDH-wild type(P=0.04). We also observed lower CS in mesenchymal glioblastoma in comparison to other subclasses. The MGMT promoter methylation was determined in 17/20(85%) glioblastoma cases. While the DKFZ group established CS of 0.9 as a cut-off for matching to methylation classes, our findings suggest lower threshold values in challenging CNS tumor cases. Our experience indicates clinical utility of MP of challenging CNS tumors as a reliable ancillary diagnostic tool in routine neuropathology practice.

scholarly journals Meningioma epigenetic grouping reveals biologic drivers and therapeutic vulnerabilities

2020 ◽  
Author(s):  
David Raleigh ◽  
Stephen Magill ◽  
Charlotte Eaton ◽  
Briana Prager ◽  
William Chen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Methylation ◽  
Central Nervous System ◽  
Nervous System ◽  
Immune Cell ◽  
Lymphatic Vessels ◽  
Intermediate Outcomes ◽  
Dna Methylation Profiling ◽  
New Treatments ◽  
Methylation Profiling

Abstract Meningiomas arising from the meningothelial central nervous system lining are the most common primary intracranial tumors, and a significant cause of neurologic morbidity and mortality1. There are no effective medical therapies for meningioma patients2,3, and new treatments have been encumbered by limited understanding of meningioma biology. DNA methylation profiling provides robust classification of central nervous system tumors4, and can elucidate targets for molecular therapy5. Here we use DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, and single-cell approaches to show meningiomas are comprised of 3 epigenetic groups with distinct clinical outcomes and biological features informing new treatments for meningioma patients. Merlin-intact meningiomas (group A, 34%) have the best outcomes and are distinguished by a novel apoptotic tumor suppressor function of NF2/Merlin. Immune-enriched meningiomas (group B, 38%) have intermediate outcomes and are distinguished by immune cell infiltration, HLA expression, and lymphatic vessels. Hypermitotic meningiomas (group C, 28%) have the worst outcomes and are distinguished by convergent genetic mechanisms misactivating the cell cycle. Consistently, we find cell cycle inhibitors block meningioma growth in cell culture, organoids, xenografts, and patients. Our results establish a framework for understanding meningioma biology, and provide preclinical rationale for new therapies to treat meningioma patients.

scholarly journals Meningioma epigenetic grouping reveals biologic drivers and therapeutic vulnerabilities

2020 ◽  
Author(s):  
Abrar Choudhury ◽  
Stephen T. Magill ◽  
Charlotte D. Eaton ◽  
Briana C. Prager ◽  
William C. Chen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Methylation ◽  
Central Nervous System ◽  
Nervous System ◽  
Immune Cell ◽  
Molecular Therapy ◽  
Intermediate Outcomes ◽  
Dna Methylation Profiling ◽  
New Treatments ◽  
Methylation Profiling

SUMMARYMeningiomas arising from the meningothelial central nervous system lining are the most common primary intracranial tumors, and a significant cause of neurologic morbidity and mortality1. There are no effective medical therapies for meningioma patients2,3, and new treatments have been encumbered by limited understanding of meningioma biology. DNA methylation profiling provides robust classification of central nervous system tumors4, and can elucidate targets for molecular therapy5. Here we use DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, and single-cell approaches to show meningiomas are comprised of 3 epigenetic groups with distinct clinical outcomes and biological features informing new treatments for meningioma patients. Merlin-intact meningiomas (group A, 34%) have the best outcomes and are distinguished by a novel apoptotic tumor suppressor function of NF2/Merlin. Immune-enriched meningiomas (group B, 38%) have intermediate outcomes and are distinguished by immune cell infiltration, HLA expression, and lymphatic vessels. Hypermitotic meningiomas (group C, 28%) have the worst outcomes and are distinguished by convergent genetic mechanisms misactivating the cell cycle. Consistently, we find cell cycle inhibitors block meningioma growth in cell culture, organoids, xenografts, and patients. Our results establish a framework for understanding meningioma biology, and provide preclinical rationale for new therapies to treat meningioma patients.

scholarly journals Analyses of DNA Methylation Profiling in the Diagnosis of Intramedullary Astrocytomas

2021 ◽  
Author(s):  
Laetitia Lebrun ◽  
Martin Bizet ◽  
Barbara Melendez ◽  
Barbara Alexiou ◽  
Lara Absil ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Central Nervous System ◽  
Cns Tumors ◽  
High Grade ◽  
Wild Type ◽  
Molecular Analyses ◽  
Classification Approach ◽  
Dna Methylation Profiling ◽  
Reference Cohort ◽  
Methylation Profiling

Abstract Intramedullary astrocytomas (IMAs) consist of a heterogeneous group of rare central nervous system (CNS) tumors associated with variable outcomes. A DNA methylation-based classification approach has recently emerged as a powerful tool to further classify CNS tumors. However, no DNA methylation-related studies specifically addressing to IMAs have been performed yet. In the present study, we analyzed 16 IMA samples subjected to morphological and molecular analyses, including DNA methylation profiling. Among the 16 samples, only 3 cases were classified in a reference methylation class (MC) with the recommended calibrated score (≥0.9). The remaining cases were either considered “no-match” cases (calibrated score &lt;0.3, n = 7) or were classified with low calibrated scores (ranging from 0.32 to 0.53, n = 6), including inconsistent classification. To obtain a more comprehensive tool for pathologists, we used different unsupervised analyses of DNA methylation profiles, including our data and those from the Heidelberg reference cohort. Even though our cohort included only 16 cases, hypotheses regarding IMA-specific classification were underlined; a potential specific MC of PA_SPINE was identified and high-grade IMAs, probably consisting of H3K27M wild-type IMAs, were mainly associated with ANA_PA MC. These hypotheses strongly suggest that a specific classification for IMAs has to be investigated.

scholarly journals A novel SMARCA2-CREM fusion: expanding the molecular spectrum of intracranial mesenchymal tumors beyond the FET genes

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Arnault Tauziède-Espariat ◽  
Gaëlle Pierron ◽  
Delphine Guillemot ◽  
Philipp Sievers ◽  
Dominique Cazals-Hatem ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Central Nervous System ◽  
Nervous System ◽  
Soft Tissue ◽  
Clear Cell ◽  
Clear Cell Sarcoma ◽  
World Health ◽  
Tumor Type ◽  
Cell Sarcoma ◽  
The Central Nervous System

AbstractA novel histomolecular tumor of the central nervous system, the “intracranial mesenchymal tumor (IMT), FET-CREB fusion-positive” has recently been identified in the literature and will be added to the 2021 World Health Organization Classification of Tumors of the Central Nervous System. However, our latest study using DNA-methylation analyses has revealed that intracranial FET-CREB fused tumors do not represent a single molecular tumor entity. Among them, the main subgroup presented classical features of angiomatoid fibrous histiocytoma, having ultrastructural features of arachnoidal cells, for. Another tumor type with clear cell component and histopathological signs of aggressivity clustered in close vicinity with clear cell sarcoma of soft tissue. Herein, we report one case of IMT with a novel SMARCA2-CREM fusion which has until now never been described in soft tissue or the central nervous system. We compare its clinical, histopathological, immunophenotypic, genetic and epigenetic features with those previously described in IMT, FET-CREB fusion-positive. Interestingly, the current case did not cluster with IMT, FET-CREB fusion-positive but rather presented histopathological (clear cell morphology with signs of malignancy), clinical (with a dismal course with several recurrences, metastases and finally the patient’s death), genetic (fusion implicating the CREM gene), and epigenetic (DNA-methylation profiling) similarities with our previously reported clear cell sarcoma-like tumor of the central nervous system. Our results added data suggesting that different clinical and histomolecular tumor subtypes or grades seem to be included within the terminology “IMT, FET-CREB fusion-positive”, and that further series of cases are needed to better characterize them.

scholarly journals The central nervous system tumor methylation classifier changes neuro-oncology practice for challenging brain tumor diagnoses and directly impacts patient care

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Shirin Karimi ◽  
Jeffrey A. Zuccato ◽  
Yasin Mamatjan ◽  
Sheila Mansouri ◽  
Suganth Suppiah ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Central Nervous System ◽  
Nervous System ◽  
Patient Care ◽  
Classification Systems ◽  
Tumor Classification ◽  
Tumor Board ◽  
Molecular Diagnostic ◽  
Cns Tumor ◽  
Methylation Profiling

Abstract Background Molecular signatures are being increasingly incorporated into cancer classification systems. DNA methylation-based central nervous system (CNS) tumor classification is being recognized as having the potential to aid in cases of difficult histopathological diagnoses. Here, we present our institutional clinical experience in integrating a DNA-methylation-based classifier into clinical practice and report its impact on CNS tumor patient diagnosis and treatment. Methods Prospective case review was undertaken at CNS tumor board discussions over a 3-year period and 55 tumors with a diagnosis that was not certain to two senior neuropathologists were recommended for methylation profiling based on diagnostic needs. Tumor classification, calibrated scores, and copy number variant (CNV) plots were obtained for all 55 cases. These results were integrated with histopathological findings to reach a final diagnosis. We retrospectively reviewed each patient's clinical course to determine final neuro-pathology diagnoses and the impact of methylation profiling on their clinical management, with a focus on changes that were made to treatment decisions. Results Following methylation profiling, 46 of the 55 (84%) challenging cases received a clinically relevant diagnostic alteration, with two-thirds having a change in the histopathological diagnosis and the other one-third obtaining clinically important molecular diagnostic or subtyping alterations. WHO grading changed by 27% with two-thirds receiving a higher grade. Patient care was directly changed in 15% of all cases with major changes in clinical decision-making being made for these patients to avoid unnecessary or insufficient treatment. Conclusions The integration of methylation-based CNS tumor classification into diagnostics has a substantial clinical benefit for patients with challenging CNS tumors while also avoiding unnecessary health care costs. The clinical impact shown here may prompt the expanded use of DNA methylation profiling for CNS tumor diagnostics within prominent neuro-oncology centers globally.

scholarly journals Acute and chronic gregarisation are associated with distinct DNA methylation fingerprints in desert locusts

2015 ◽  
Author(s):  
Eamonn B. Mallon ◽  
Harindra E. Amarasinghe ◽  
Swidbert R. Ott
Keyword(s):  
Dna Methylation ◽  
Central Nervous System ◽  
Nervous System ◽  
Schistocerca Gregaria ◽  
Dramatic Form ◽  
Length Polymorphisms ◽  
Amplified Fragment Length Polymorphisms ◽  
Intermediate States ◽  
The Central Nervous System ◽  
Phase Polyphenism

AbstractDesert locusts (Schistocerca gregaria) show a dramatic form of socially induced phenotypic plasticity known as phase polyphenism. In the absence of conspecifics, locusts occur in a shy and cryptic solitarious phase. Crowding with conspecifics drives a behavioural transformation towards gregariousness that occurs within hours and is followed by changes in physiology, colouration and morphology, resulting in the full gregarious phase syndrome. We analysed methylation-sensitive amplified fragment length polymorphisms (MS-AFLP) to compare the effect of acute and chronic crowding on DNA methylation in the central nervous system. We find that crowd-reared and solitary-reared locusts show markedly different neural MS-AFLP fingerprints. However, crowding for a day resulted in neural MS-AFLP fingerprints that were clearly distinct from both crowd-reared and uncrowded solitary-reared locusts. Our results indicate that changes in DNA methylation associated with behavioural gregarisation proceed through intermediate states that are not simply partial realisations of the endpoint states.

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