DNA methylation temporal profiling following peripheral versus central nervous system axotomy

Abstract Purpose High-grade astrocytoma with piloid features (HGAP) is a recently described brain tumor entity defined by a specific DNA methylation profile. HGAP has been proposed to be integrated in the upcoming World Health Organization classification of central nervous system tumors expected in 2021. In this series, we present the first single-center experience with this new entity. Methods During 2017 and 2020, six HGAP were identified. Clinical course, surgical procedure, histopathology, genome-wide DNA methylation analysis, imaging, and adjuvant therapy were collected. Results Tumors were localized in the brain stem (n = 1), cerebellar peduncle (n = 1), diencephalon (n = 1), mesencephalon (n = 1), cerebrum (n = 1) and the thoracic spinal cord (n = 2). The lesions typically presented as T1w hypo- to isointense and T2w hyperintense with inhomogeneous contrast enhancement on MRI. All patients underwent initial surgical intervention. Three patients received adjuvant radiochemotherapy, and one patient adjuvant radiotherapy alone. Four patients died of disease, with an overall survival of 1.8, 9.1, 14.8 and 18.1 months. One patient was alive at the time of last follow-up, 14.6 months after surgery, and one patient was lost to follow-up. Apart from one tumor, the lesions did not present with high grade histology, however patients showed poor clinical outcomes. Conclusions Here, we provide detailed clinical, neuroradiological, histological, and molecular pathological information which might aid in clinical decision making until larger case series are published. With the exception of one case, the tumors did not present with high-grade histology but patients still showed short intervals between diagnosis and tumor progression or death even after extensive multimodal therapy.

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DNA methylation-based classification of central nervous system tumours

Nature ◽

10.1038/nature26000 ◽

2018 ◽

Vol 555 (7697) ◽

pp. 469-474 ◽

Cited By ~ 579

Author(s):

David Capper ◽

David T. W. Jones ◽

Martin Sill ◽

Volker Hovestadt ◽

Daniel Schrimpf ◽

...

Keyword(s):

Dna Methylation ◽

Central Nervous System ◽

Nervous System ◽

Central Nervous System Tumours

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Histologically defined central nervous system primitive neuro-ectodermal tumours (CNS-PNETs) display heterogeneous DNA methylation profiles and show relationships to other paediatric brain tumour types

Acta Neuropathologica ◽

10.1007/s00401-013-1206-6 ◽

2013 ◽

Vol 126 (6) ◽

pp. 943-946 ◽

Cited By ~ 20

Author(s):

Ed. C. Schwalbe ◽

James T. Hayden ◽

Hazel A. Rogers ◽

Suzanne Miller ◽

Janet C. Lindsey ◽

...

Keyword(s):

Dna Methylation ◽

Central Nervous System ◽

Nervous System ◽

Brain Tumour ◽

Paediatric Brain Tumour

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The case for DNA methylation based molecular profiling to improve diagnostic accuracy for central nervous system embryonal tumors (not otherwise specified) in adults

Journal of Clinical Neuroscience ◽

10.1016/j.jocn.2017.09.013 ◽

2018 ◽

Vol 47 ◽

pp. 163-167 ◽

Cited By ~ 3

Author(s):

Gail C. Halliday ◽

Reimar C. Junckerstorff ◽

Jacqueline M. Bentel ◽

Andrew Miles ◽

David T.W. Jones ◽

...

Keyword(s):

Dna Methylation ◽

Central Nervous System ◽

Nervous System ◽

Diagnostic Accuracy ◽

Molecular Profiling ◽

Embryonal Tumors ◽

Not Otherwise Specified

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Proteins in DNA methylation and their role in neural stem cell proliferation and differentiation

Cell Regeneration ◽

10.1186/s13619-020-00070-4 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Jiaqi Sun ◽

Junzheng Yang ◽

Xiaoli Miao ◽

Horace H. Loh ◽

Duanqing Pei ◽

...

Keyword(s):

Dna Methylation ◽

Central Nervous System ◽

Nervous System ◽

Brain Plasticity ◽

Dna Methyltransferases ◽

Fine Tuning ◽

Mammalian Brain ◽

Main Body ◽

Sequencing Technologies ◽

Proliferation And Differentiation

Abstract Background Epigenetic modifications, namely non-coding RNAs, DNA methylation, and histone modifications such as methylation, phosphorylation, acetylation, ubiquitylation, and sumoylation play a significant role in brain development. DNA methyltransferases, methyl-CpG binding proteins, and ten-eleven translocation proteins facilitate the maintenance, interpretation, and removal of DNA methylation, respectively. Different forms of methylation, including 5-methylcytosine, 5-hydroxymethylcytosine, and other oxidized forms, have been detected by recently developed sequencing technologies. Emerging evidence suggests that the diversity of DNA methylation patterns in the brain plays a key role in fine-tuning and coordinating gene expression in the development, plasticity, and disorders of the mammalian central nervous system. Neural stem cells (NSCs), originating from the neuroepithelium, generate neurons and glial cells in the central nervous system and contribute to brain plasticity in the adult mammalian brain. Main body Here, we summarized recent research in proteins responsible for the establishment, maintenance, interpretation, and removal of DNA methylation and those involved in the regulation of the proliferation and differentiation of NSCs. In addition, we discussed the interactions of chemicals with epigenetic pathways to regulate NSCs as well as the connections between proteins involved in DNA methylation and human diseases. Conclusion Understanding the interplay between DNA methylation and NSCs in a broad biological context can facilitate the related studies and reduce potential misunderstanding.

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Differential and Common Signatures of miRNA Expression and Methylation in Childhood Central Nervous System Malignancies: An Experimental and Computational Approach

Cancers ◽

10.3390/cancers13215491 ◽

2021 ◽

Vol 13 (21) ◽

pp. 5491

Author(s):

George I. Lambrou ◽

Myrto Poulou ◽

Krinio Giannikou ◽

Marios Themistocleous ◽

Apostolos Zaravinos ◽

...

Keyword(s):

Dna Methylation ◽

Central Nervous System ◽

Nervous System ◽

Mirna Expression ◽

Tumor Staging ◽

Gene Promoter ◽

Tumor Type ◽

Gene Methylation ◽

Microarray Screening ◽

And Control

Epigenetic modifications are considered of utmost significance for tumor ontogenesis and progression. Especially, it has been found that miRNA expression, as well as DNA methylation plays a significant role in central nervous system tumors during childhood. A total of 49 resected brain tumors from children were used for further analysis. DNA methylation was identified with methylation-specific MLPA and, in particular, for the tumor suppressor genes CASP8, RASSF1, MGMT, MSH6, GATA5, ATM1, TP53, and CADM1. miRNAs were identified with microarray screening, as well as selected samples, were tested for their mRNA expression levels. CASP8, RASSF1 were the most frequently methylated genes in all tumor samples. Simultaneous methylation of genes manifested significant results with respect to tumor staging, tumor type, and the differentiation of tumor and control samples. There was no significant dependence observed with the methylation of one gene promoter, rather with the simultaneous presence of all detected methylated genes’ promoters. miRNA expression was found to be correlated to gene methylation. Epigenetic regulation appears to be of major importance in tumor progression and pathophysiology, making it an imperative field of study.

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

Neuro-Oncology ◽

10.1093/neuonc/noz175.617 ◽

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.

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

BMC Cancer ◽

10.1186/1471-2407-9-455 ◽

2009 ◽

Vol 9 (1) ◽

Cited By ~ 19

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

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

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01278-4 ◽

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.

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