EPCO-01. MOLECULAR PROFILING OF SPINAL CORD EPENDYMOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi1-vi1
Author(s):  
Erika Yamazawa ◽  
Shota Tanaka ◽  
Genta Nagae ◽  
Takayoshi Umeda ◽  
Taijun Hana ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Dna Methylation ◽  
Methylation Status ◽  
Neurofibromatosis Type ◽  
Methylation Pattern ◽  
Who Grade ◽  
Spinal Ependymoma ◽  
Fresh Frozen ◽  
Spinal Cord Ependymoma ◽  
The Difference

Abstract BACKGROUND Ependymomas are currently classified into 9 subgroups by DNA methylation profiles. Although spinal cord ependymoma (SP-EPN) is distinct from other tumors, diversity within SP-EPN is still unclear. Here, we used transcriptomic and epigenomic profiles to investigate the diversity among Japanese SP-EPN cases. MATERIALS AND METHODS We analyzed 57 SP-EPN patients (32 males and 25 females, aged from 18 to 78 years, median: 52), including two cases of neurofibromatosis type 2, five cases of grade 3 (WHO grade). We obtained transcriptome (RNA-seq) and DNA methylation (Infinium Methylation EPIC array) data from fresh frozen specimens of SP-EPN resected at the University of Tokyo Hospital and our collaborative groups. RESULTS Three cases had a previous intracranial ependymoma operation. Hierarchical clustering of the DNA methylation data showed that these three cases of intracranial origin as a different cluster from spinal origin. The 45 grade 2 spinal ependymoma showed a relatively homogenous methylation pattern. However, the methylation status of HOX gene cluster regions is compatible with the segment of origin, which reflects the cells of origins are derived after the determination of segment identity. RNA sequencing of 57 cases revealed two subgroups within grade 2. Gene ontology analysis of differentially expressed genes suggested the difference in metabolic state such as rRNA translation and mitochondrial respiration between the two expression subgroups. CONCLUSION Epigenetic analysis indicated the accurate body segment origin of SP-EPN. We observed that metabolic states could divide grade 2 spinal cord ependymoma into 2 subgroups and will present the relationship to clinicopathological information.

scholarly journals PATH-33. EPIGENOMIC ANALYSIS OF SPINAL EPENDYMOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii171-ii171
Author(s):  
Erika Yamazawa ◽  
Shota Tanaka ◽  
Nagae Genta ◽  
Meguro Hiroko ◽  
Takayoshi Umeda ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Dna Methylation ◽  
Profile Analysis ◽  
Neurofibromatosis Type ◽  
Methylation Data ◽  
Who Grade ◽  
Spinal Ependymoma ◽  
Dna Methylation Profile ◽  
Spinal Cord Ependymoma ◽  
The University

Abstract BACKGROUND Ependymomas commonly occur in the fourth ventricle and the spinal cord. Gross total resection, age and WHO grade are known prognostic factors. Ependymomas are currently classified into 9 distinct subgroups by DNA methylation profile analysis. Spinal cord ependymoma is distinct from other subgroups. To investigate heterogeneity within spinal cord ependymoma, we examined DNA methylation profiles. MATERIALS AND METHODS We used Infinium MethylationEPIC array (illumina) to obtain DNA methylation data from frozen specimens of spinal ependymoma resected at the University of Tokyo, Osaka City University, and Tokyo Metropolitan Neurological Hospital. Japan Pediatric Molecular Neuro-Oncology Group provided methylation data for 11 reported cases. Cluster analysis was performed using Cluster3.0. RESULTS We analyzed 34 patients, 21 male and 13 female, aged from 18 to 76 years (median 50.5 years), including 2 cases with neurofibromatosis type 2. WHO grade was grade_3 in 2 cases and grade_2 in others. Clustering of the DNA methylation data showed that WHO grade_3 cases tended to be classified into a subgroup distinct from other cases. CONCLUSION This is the largest DNA methylation profiling study on spinal cord ependymoma to date. The study may suggest a new subgroup correlated with higher WHO grade.

scholarly journals Signatures of polycomb repression and reduced H3K4 trimethylation are associated with p15INK4b DNA methylation in AML

Blood ◽  
2010 ◽  
Vol 115 (15) ◽  
pp. 3098-3108 ◽  
Author(s):  
Thomas A. Paul ◽  
Juraj Bies ◽  
Donald Small ◽  
Linda Wolff
Keyword(s):  
Dna Methylation ◽  
Histone Modifications ◽  
Transcriptional Repression ◽  
Trichostatin A ◽  
Methylation Status ◽  
Suppressor Gene ◽  
Methylation Pattern ◽  
Dna Hypermethylation ◽  
Polycomb Repression ◽  
On Chip

Abstract DNA hypermethylation of the p15INK4b tumor suppressor gene is commonly observed in acute myeloid leukemia (AML). Repressive histone modifications and their associated binding proteins have been implicated in the regulation of DNA methylation and the transcriptional repression of genes with DNA methylation. We have used high-density chromatin immunoprecipitation-on-chip to determine the histone modifications that normally regulate p15INK4b expression in AML cells and how these marks are altered in cells that have p15INK4b DNA methylation. In AML patient blasts without p15INK4b DNA methylation, a bivalent pattern of active (H3K4me3) and repressive (H3K27me3) modifications exist at the p15INK4b promoter. AML patient blasts with p15INK4b DNA methylation lose H3K4me3 at p15INK4b and become exclusively marked by H3K27me3. H3K27me3, as well as EZH2, extends throughout p14ARF and p16INK4a, indicating that polycomb repression of p15INK4b is a common feature in all AML blasts irrespective of the DNA methylation status of the gene. Reactivation of p15INK4b expression in AML cell lines and patient blasts using 5-aza-2′-deoxycytidine (decitabine) and trichostatin A increased H3K4me3 and maintained H3K27me3 enrichment at p15INK4b. These data indicate that AML cells with p15INK4b DNA methylation have an altered histone methylation pattern compared with unmethylated samples and that these changes are reversible by epigenetic drugs.

scholarly journals Deoxyribonucleic Acid Methylation Controls Cell Type-Specific Expression of Steroidogenic Factor 1

Endocrinology ◽  
2008 ◽  
Vol 149 (11) ◽  
pp. 5599-5609 ◽  
Author(s):  
Erling A. Hoivik ◽  
Linda Aumo ◽  
Reidun Aesoy ◽  
Haldis Lillefosse ◽  
Aurélia E. Lewis ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Rna Polymerase Ii ◽  
Methylation Status ◽  
Endocrine System ◽  
Methylation Pattern ◽  
Proximal Promoter ◽  
Specific Expression ◽  
Steroidogenic Factor 1 ◽  
In Cells

Steroidogenic factor 1 (SF1) is expressed in a time- and cell-specific manner in the endocrine system. In this study we present evidence to support that methylation of CpG sites located in the proximal promoter of the gene encoding SF1 contributes to the restricted expression pattern of this nuclear receptor. DNA methylation analyses revealed a nearly perfect correlation between the methylation status of the proximal promoter and protein expression, such that it was hypomethylated in cells that express SF1 but hypermethylated in nonexpressing cells. Moreover, in vitro methylation of this region completely repressed reporter gene activity in transfected steroidogenic cells. Bisulfite sequencing of DNA from embryonic tissue demonstrated that the proximal promoter was unmethylated in the developing testis and ovary, whereas it was hypermethylated in tissues that do not express SF1. Together these results indicate that the DNA methylation pattern is established early in the embryo and stably inherited thereafter throughout development to confine SF1 expression to the appropriate tissues. Chromatin immunoprecipitation analyses revealed that the transcriptional activator upstream stimulatory factor 2 and RNA polymerase II were specifically recruited to this DNA region in cells in which the proximal promoter is hypomethylated, providing functional support for the fact that lack of methylation corresponds to a transcriptionally active gene. In conclusion, we identified a region within the SF1/Sf1 gene that epigenetically directs cell-specific expression of SF1.

scholarly journals ATM Mediates pRB Function To Control DNMT1 Protein Stability and DNA Methylation

2013 ◽  
Vol 33 (16) ◽  
pp. 3113-3124 ◽  
Author(s):  
Awad Shamma ◽  
Misa Suzuki ◽  
Naoyuki Hayashi ◽  
Masahiko Kobayashi ◽  
Nobunari Sasaki ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Protein Stability ◽  
Genetic Interaction ◽  
Methylation Status ◽  
Tumor Model ◽  
Suppressor Gene ◽  
Methylation Pattern ◽  
Control Of Gene Expression ◽  
Retinoblastoma Tumor Suppressor ◽  
Retinoblastoma Tumor

The retinoblastoma tumor suppressor gene (RB) product has been implicated in epigenetic control of gene expression owing to its ability to physically bind to many chromatin modifiers. However, the biological and clinical significance of this activity was not well elucidated. To address this, we performed genetic and epigenetic analyses in anRb-deficient mouse thyroid C cell tumor model. Here we report that the genetic interaction ofRbandATMregulates DNMT1 protein stability and hence controls the DNA methylation status in the promoters of at least theInk4a,Shc2,FoxO6, andNoggingenes. Furthermore, we demonstrate that inactivation of pRB promotes Tip60 (acetyltransferase)-dependent ATM activation; allows activated ATM to physically bind to DNMT1, forming a complex with Tip60 and UHRF1 (E3 ligase); and consequently accelerates DNMT1 ubiquitination driven by Tip60-dependent acetylation. Our results indicate that inactivation of the pRB pathway in coordination with aberration in the DNA damage response deregulates DNMT1 stability, leading to an abnormal DNA methylation pattern and malignant progression.

scholarly journals The response of spinal cord ependymomas to bevacizumab in patients with neurofibromatosis Type 2

2017 ◽  
Vol 26 (4) ◽  
pp. 474-482 ◽  
Author(s):  
Katrina A. Morris ◽  
Shazia K. Afridi ◽  
D. Gareth Evans ◽  
Anke E. Hensiek ◽  
Martin G. McCabe ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neurofibromatosis Type ◽  
Neurofibromatosis Type 2 ◽  
Response To Treatment ◽  
Spinal Ependymoma ◽  
Bevacizumab Treatment ◽  
Radiological Changes ◽  
And Behavior ◽  
Serial Images

OBJECTIVE People with neurofibromatosis Type 2 (NF2) have a genetic predisposition to nervous system tumors. NF2-associated schwannomas stabilize or decrease in size in over half of the patients while they are receiving bevacizumab. NF2 patients treated with bevacizumab for rapidly growing schwannoma were retrospectively reviewed with regard to ependymoma prevalence and response to treatment. METHODS The records of 95 NF2 patients receiving bevacizumab were retrospectively reviewed with regard to spinal ependymoma prevalence and behavior. The maximum longitudinal extent (MLE) of the ependymoma and associated intratumoral or juxtatumoral cysts were measured on serial images. Neurological changes and patient function were reviewed and correlated with radiological changes. RESULTS Forty-one of 95 patients were found to have ependymomas (median age 26 years; range 11–53 years). Thirty-two patients with a total of 71 ependymomas had scans appropriate for serial assessment with a mean follow-up of 24 months (range 3–57 months). Ependymomas without cystic components showed minimal change in MLE. Twelve patients had ependymomas with cystic components or syringes. In these patients, reductions in MLE were observed, particularly due to decreases in the cystic components of the ependymoma. Clinical improvement was seen in 7 patients, who all had cystic ependymomas. CONCLUSIONS Bevacizumab treatment in NF2 patients with spinal cord ependymomas results in a decrease in the size of intratumoral and juxtatumoral cysts as well as adjacent-cord syringes and a decrease in cord edema. This may provide clinical benefit in some patients, although the changes do not meet the current criteria for radiological tumor response.

Search for methylation-sensitive amplification polymorphisms associated with the "mantled" variant phenotype in oil palm (Elaeis guineensis Jacq.)

Genome ◽  
2004 ◽  
Vol 47 (1) ◽  
pp. 224-228 ◽  
Author(s):  
E Jaligot ◽  
T Beulé ◽  
F-C Baurens ◽  
N Billotte ◽  
A Rival
Keyword(s):  
Dna Methylation ◽  
Somaclonal Variation ◽  
Oil Palm ◽  
Elaeis Guineensis ◽  
Methylation Status ◽  
Methylation Pattern ◽  
Variant Phenotype ◽  
Elaeis Guineensis Jacq ◽  
The Moment ◽  
Direct Use

The methylation-sensitive amplification polymorphism (MSAP) technique has been employed on somatic embryo-derived oil palms (Elaeis guineensis Jacq.) to identify methylation polymorphisms correlated with the "mantled" somaclonal variation. The variant phenotype displays an unstable feminization of male organs in both male and female flowers. Using MSAP, the methylation status of CCGG sites was compared in three normal versus three mantled regenerants sampled in clonal populations obtained through somatic embryogenesis from four genotypically distinct mother palms. Overall, 64 selective primer combinations were used and they have amplified 23 markers exhibiting a differential methylation pattern between the two phenotypes. Our results indicate that CCGG sites are poorly affected by the considerable decrease in global DNA methylation that has been previously associated with the mantled phenotype. Each of the 23 markers isolated in the present study could discriminate between the two phenotypes only when they were from the same genetic origin. This result hampers at the moment the direct use of MSAP markers for the early detection of variants, even though valuable information on putative target sequences will be obtained from a further characterization of these polymorphic markers.Key words: DNA methylation, epigenetics, MSAP, oil palm, somaclonal variation.

scholarly journals Methylation of AR locus does not always reflect X chromosome inactivation state

Blood ◽  
2012 ◽  
Vol 119 (13) ◽  
pp. e100-e109 ◽  
Author(s):  
Sabina I. Swierczek ◽  
Lucie Piterkova ◽  
Jaroslav Jelinek ◽  
Neeraj Agarwal ◽  
Sue Hammoud ◽  
...  
Keyword(s):  
Dna Methylation ◽  
X Chromosome ◽  
Elderly Women ◽  
Methylation Status ◽  
Methylation Pattern ◽  
Elderly Persons ◽  
Quantitative Expression ◽  
Clonal Hematopoiesis ◽  
Healthy Elderly ◽  
Gene Assay

Abstract Clonality can be established by a lack of mosaicism in a female because of random inactivation of either the maternal or paternal X chromosome early in embryogenesis. The methylation status of CpG sites close to the trinucleotide repeats in exon 1 of the human androgen receptor (AR) X chromosome gene assay (HUMARA) has been used to determine clonality. This HUMARA at times indicated clonal hematopoiesis in healthy elderly women, thus precluding its applicability. We used a clonality assay based on quantitative expression of polymorphic X chromosome genes (qTCA) and found no evidence of clonal hematopoiesis in healthy nonanemic elderly persons. We found instances of discordance between HUMARA results and those obtained by pyrosequencing and qTCA methods, as well as by directly quantifying AR gene expression. To determine the basis of this discrepancy we examined the methylation pattern of the AR locus subject to HUMARA. Notably, we found the extent of DNA methylation to be highly variable at the AR gene in granulocytes of persons with discordant results and also in erythroid burst-forming unit colonies but not in those with clonal hematopoiesis. These data provide the molecular basis of incomplete correlation with the pattern of DNA methylation of this X chromosome AR gene locus.

scholarly journals Activation of hypermethylated P2RY1 mitigates gastric cancer by promoting apoptosis and inhibiting proliferation

2021 ◽  
Author(s):  
yinggang hua ◽  
yanling liu ◽  
long li ◽  
guoyan liu
Keyword(s):  
Gastric Cancer ◽  
Dna Methylation ◽  
Promoter Region ◽  
Methylation Status ◽  
Diffuse Gastric Cancer ◽  
Normal Tissues ◽  
The Difference ◽  
Diffuse Type Gastric Cancer ◽  
Cancer Tissues ◽  
Erk Signal Pathway

Abstract Background P2RY1 receptor is known to cause cancer by activating the ERK signal pathway, its DNA methylation status or even the corresponding regulatory mechanism remains unknown. Methods In this study, DNA methylation chip was used to profile the genome-wide DNA methylation level in gastric cancer tissues. Then validated by the bioinformatics analysis in the TCGA database, Immunohistochemistry staining data obtained from the HPA database to verify the difference in protein expression between normal tissues and tumor tissues . Results The promoter region of P2RY1 was found to be highly methylated with 4 hypermethylated sites (|Δβ value| >0.2) in diffuse gastric cancer and the expression level of P2RY1 is relatively low compared with non-cancerous tissues. We also showed that MRS2365, a selective agonist of the P2RY1 receptor, can induce phosphorylation of ERK1/2, inhibit cell proliferation/migration and induce apoptosis. Conclusion High DNA methylation in the promoter region of P2RY1 may have contributed to the reduced expression of P2RY1’s mRNA, which is likely responsible for the “aggressive” nature of the diffuse type gastric cancer.

Variety of preoperative MRI changes in spinal cord ependymoma of WHO grade II: a case series

2018 ◽  
Vol 28 (2) ◽  
pp. 426-433 ◽  
Author(s):  
Kazuyoshi Kobayashi ◽  
Kei Ando ◽  
Fumihiko Kato ◽  
Koji Sato ◽  
Mitsuhiro Kamiya ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Case Series ◽  
Who Grade ◽  
Grade Ii ◽  
Spinal Cord Ependymoma ◽  
Mri Changes
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