Clinically aggressive pediatric spinal ependymoma with novel MYC amplification demonstrates molecular and histopathologic similarity to newly described MYCN-amplified spinal ependymomas

AbstractPrimary spinal cord tumors contribute to ≤ 10% of central nervous system tumors in individuals of pediatric or adolescent age. Among intramedullary tumors, spinal ependymomas make up ~ 30% of this rare tumor population. A twelve-year-old male presented with an intradural, extramedullary mass occupying the dorsal spinal canal from C6 through T2. Gross total resection and histopathology revealed a World Health Organization (WHO) grade 2 ependymoma. He recurred eleven months later with extension from C2 through T1-T2. Subtotal resection was achieved followed by focal proton beam irradiation and chemotherapy. Histopathology was consistent with WHO grade 3 ependymoma. Molecular profiling of the primary and recurrent tumors revealed a novel amplification of the MYC (8q24) gene, which was confirmed by fluorescence in situ hybridization studies. Although MYC amplification in spinal ependymoma is exceedingly rare, a newly described classification of spinal ependymoma harboring MYCN (2p24) amplification (SP-MYCN) has been defined by DNA methylation-array based profiling. These individuals typically present with a malignant progression and dismal outcomes, contrary to the universally excellent survival outcomes seen in other spinal ependymomas. DNA methylation array-based classification confidently classified this tumor as SP-MYCN ependymoma. Notably, among the cohort of 52 tumors comprising the SP-MYCN methylation class, none harbor MYC amplification, highlighting the rarity of this genomic amplification in spinal ependymoma. A literature review comparing our individual to reported SP-MYCN tumors (n = 26) revealed similarities in clinical, histopathologic, and molecular features. Thus, we provide evidence from a single case to support the inclusion of MYC amplified spinal ependymoma within the molecular subgroup of SP-MYCN.

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RARE-54. MOLECULAR ANALYSIS OF ROSETTE-FORMING GLIONEURONAL TUMOR AT MIDBRAIN; REPORT OF TWO CASES

Neuro-Oncology ◽

10.1093/neuonc/noaa222.764 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii454-iii454

Author(s):

Hajime Handa

Keyword(s):

Dna Methylation ◽

Histological Analysis ◽

Clinical Course ◽

Methylation Status ◽

Glioneuronal Tumor ◽

Rt Pcr ◽

Methylation Array ◽

Molecular Features ◽

Occipital Transtentorial Approach ◽

Dna Methylation Array

Abstract Rosette-forming glioneuronal tumor (RGNT) is a tumor that primarily arises at posterior fossa. We experienced two rare cases of RGNT located at midbrain and investigated their molecular features. Case 1 is a 23-year-old female, and Case 2 is an 18-year-old male. Both cases were surgically removed by the occipital transtentorial approach. Histological analysis demonstrated a biphasic pattern of neurocytic and glial components. The former consisted of neurocytic rosettes and perivascular pseudorosettes, and the latter was GFAP positive, corresponding to the diagnosis of RGNT. Both cases have an excellent clinical course without receiving chemotherapy or radiation therapy. Small residual tumors of both cases shrunk and maintained for 27 and 12 months, respectively. Case 1 underwent DNA methylation array and a subsequent DNA methylation-based classifier, indicating that the case matched RGNT with a 0.99 calibrated score. Also, we identified FGFR1 K656 mutation. Pyrosequence analysis of other genes such as IDH1 R132, IDH2 R172, BRAF T599, BRAF V600, H3F3A K27, H3F3A G34, HIST1H3B K27, TERT C228, FGFR1 N546 had no mutations. RT-PCR of KIAA1549-BRAF fusion was not detected. DNA methylation status of Case 2 is under investigation. Pyorosequence analysis identified TERT C228 mutation but did not identify other mutations such as FGFR1 N546 and K656. Midbrain RGNT corresponds to the histological and molecular features of RGNT. RGNT needs to be differentially diagnosed in the case of a midbrain tumor.

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EWAS Data Hub: a resource of DNA methylation array data and metadata

Nucleic Acids Research ◽

10.1093/nar/gkz840 ◽

2019 ◽

Vol 48 (D1) ◽

pp. D890-D895 ◽

Cited By ~ 6

Author(s):

Zhuang Xiong ◽

Mengwei Li ◽

Fei Yang ◽

Yingke Ma ◽

Jian Sang ◽

...

Keyword(s):

Dna Methylation ◽

Complex Traits ◽

Cell Types ◽

Great Promise ◽

Methylation Array ◽

Array Data ◽

The Past ◽

Comprehensive Collection ◽

Dna Methylation Array ◽

Brain Parts

Abstract Epigenome-Wide Association Study (EWAS) has become an effective strategy to explore epigenetic basis of complex traits. Over the past decade, a large amount of epigenetic data, especially those sourced from DNA methylation array, has been accumulated as the result of numerous EWAS projects. We present EWAS Data Hub (https://bigd.big.ac.cn/ewas/datahub), a resource for collecting and normalizing DNA methylation array data as well as archiving associated metadata. The current release of EWAS Data Hub integrates a comprehensive collection of DNA methylation array data from 75 344 samples and employs an effective normalization method to remove batch effects among different datasets. Accordingly, taking advantages of both massive high-quality DNA methylation data and standardized metadata, EWAS Data Hub provides reference DNA methylation profiles under different contexts, involving 81 tissues/cell types (that contain 25 brain parts and 25 blood cell types), six ancestry categories, and 67 diseases (including 39 cancers). In summary, EWAS Data Hub bears great promise to aid the retrieval and discovery of methylation-based biomarkers for phenotype characterization, clinical treatment and health care.

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MBRS-14. INTEGRATING CLINICAL AND GENOMIC CHARACTERISTICS IN PEDIATRIC MEDULLOBLASTOMA SUBTYPES IN A SINGLE COHORT IN TAIWAN

Neuro-Oncology ◽

10.1093/neuonc/noaa222.531 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii400-iii401

Author(s):

Kuo-Sheng Wu ◽

Tai-Tong Wong

Keyword(s):

Dna Methylation ◽

Cluster Analysis ◽

Treatment Strategies ◽

Clinical Results ◽

Tumor Location ◽

Molecular Subgroups ◽

Methylation Array ◽

Metastatic Rate ◽

Pediatric Medulloblastoma ◽

Dna Methylation Array

Abstract BACKGROUND Medulloblastoma (MB) was classified to 4 molecular subgroups: WNT, SHH, group 3 (G3), and group 4 (G4) with the demographic and clinical differences. In 2017, The heterogeneity within MB was proposed, and 12 subtypes with distinct molecular and clinical characteristics. PATIENTS AND METHODS: PATIENTS AND METHODS We retrieved 52 MBs in children to perform RNA-Seq and DNA methylation array. Subtype cluster analysis performed by similarity network fusion (SNF) method. With clinical results and molecular profiles, the characteristics including age, gender, histological variants, tumor location, metastasis status, survival, cytogenetic and genetic aberrations among MB subtypes were identified. RESULTS In this cohort series, 52 childhood MBs were classified into 11 subtypes by SNF cluster analysis. WNT tumors shown no metastasis and 100% survival rate. All WNT tumors located on midline in 4th ventricle. Monosomy 6 presented in WNT α, but not in β subtype. SHH α and β occurred in children, while SHH γ in infant. Among SHH tumors, α subtype showed the worst outcome. G3 γ showed the highest metastatic rate and worst survival associated with MYC amplification. G4 α has the highest metastatic rate, however G4 γ showed the worst survival. CONCLUSION We identified molecular subgroups and subtypes of MBs based on gene expression and DNA methylation profile in children in our cohort series. The results may contribute to the establishment of nation-wide correlated optimal diagnosis and treatment strategies for MBs in infant and children.

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EPCO-01. MOLECULAR PROFILING OF SPINAL CORD EPENDYMOMA

Neuro-Oncology ◽

10.1093/neuonc/noab196.000 ◽

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.

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Model-Based Clustering of DNA Methylation Array Data

Translational Bioinformatics - Computational and Statistical Epigenomics ◽

10.1007/978-94-017-9927-0_5 ◽

2015 ◽

pp. 91-123

Author(s):

Devin C. Koestler ◽

E. Andrés Houseman

Keyword(s):

Dna Methylation ◽

Methylation Array ◽

Array Data ◽

Model Based Clustering ◽

Model Based ◽

Dna Methylation Array

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Abstract LB-176: A novel high density DNA methylation array with single CpG site resolution

10.1158/1538-7445.am2011-lb-176 ◽

2011 ◽

Cited By ~ 3

Author(s):

Marina Bibikova ◽

Bret Barnes ◽

Chan Tsan ◽

Vincent Ho ◽

Brandy Klotzle ◽

...

Keyword(s):

Dna Methylation ◽

High Density ◽

Methylation Array ◽

Cpg Site ◽

Dna Methylation Array

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PATH-65. MOLECULAR SIGNATURE OF FAT1 RELATED MOLECULES IN GLIOMAS IN THE CONTEXT OF THE WHO 2016 CLASSIFICATION

Neuro-Oncology ◽

10.1093/neuonc/noz175.660 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi158-vi158

Author(s):

Kunzang Chosdol ◽

Manvi Arora ◽

Nargis Malik ◽

Prerana Jha ◽

Jyotsna Singh ◽

...

Keyword(s):

Molecular Markers ◽

In Silico Analysis ◽

Molecular Signature ◽

World Health ◽

Low Grade ◽

Who Grade ◽

Inflammatory Microenvironment ◽

Molecular Features

Abstract Glioblastoma (GBM, WHO grade-IV) being the most malignant and aggressive form of glioma remains a major clinical challenge, with an overall 5-year survival rate of only 9.8%. Till recently, glioma diagnosis and grading were solely dependent on the phenotypic and histological features. However, with the advancement in the understanding of the molecular biology of glioma several molecules have been identified. The importance of these molecular/genotypic features of the tumor became evident by the inclusion of these molecular features by World Health Organization (WHO) in 2016 in glioma sub-grouping. Our lab is focused on studying the role of FAT1 gene (human ortholog of Drosophila tumor suppressor gene, fat) in glioma biology and aggressiveness. We observed FAT1 gene to have an oncogenic role in glioma where it has been found to upregulate migration/invasion, inflammatory microenvironment of the tumors, HIF1α expression/activity in the tumor-cells under severe hypoxia and in regulating EMT/stemness properties of GBM-cells under hypoxia. Here, we have characterized the molecular relationship between FAT1 related molecules and known- molecular markers of glioma with the hope of identifying glioma subgroup with a molecular signature of clinical significance by (i) analyzing the expression correlation of FAT1 and FAT1 regulated pro-inflammatroy molecules like COX2, IL1b and IL6 with the known- molecular markers of glioma like p53, IDH1, MGMT, EGFR, TERT in low-grade (grade-II) and high-grade (grade-III/IV) gliomas (n=50) by real-time PCR, sequencing, immunohistochemistry and in-silico analysis of TCGA-GBM-data (ii) Analyzed the regulatory role of FAT1 on the above known markers by siRNA mediated knockdown of FAT1 in in-vitro cell-culture system and (iii) further analyzed the identified molecular signature for their correlation with the patients prognosis/survival in the follow up patients. We observed a novel molecular signature with significant correlation with patients’ clinical outcome. Therapeutic targetting of FAT1 may benefit patients with high FAT1 expressing tumors.

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DNA methylation array analysis identifies breast cancer associated RPTOR, MGRN1 and RAPSN hypomethylation in peripheral blood DNA

Oncotarget ◽

10.18632/oncotarget.11640 ◽

2016 ◽

Vol 7 (39) ◽

pp. 64191-64202 ◽

Cited By ~ 19

Author(s):

Qiuqiong Tang ◽

Tim Holland-Letz ◽

Alla Slynko ◽

Katarina Cuk ◽

Frederik Marme ◽

...

Keyword(s):

Breast Cancer ◽

Dna Methylation ◽

Peripheral Blood ◽

Array Analysis ◽

Methylation Array ◽

Dna Methylation Array

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High Efficacy of Fractionated Stereotactic Radiotherapy of Large Base-of-Skull Meningiomas: Long-Term Results

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.15.3547 ◽

2001 ◽

Vol 19 (15) ◽

pp. 3547-3553 ◽

Cited By ~ 197

Author(s):

Juergen Debus ◽

Martina Wuendrich ◽

Andrea Pirzkall ◽

Angelika Hoess ◽

Wolfgang Schlegel ◽

...

Keyword(s):

Skull Base ◽

Stereotactic Radiotherapy ◽

Fractionated Stereotactic Radiotherapy ◽

World Health ◽

Long Term Results ◽

Subtotal Resection ◽

Who Grade ◽

Skull Base Meningiomas

PURPOSE: Large skull-base meningiomas are difficult to treat due to their proximity or adherence to critical structures. We analyzed the long-term results of patients with skull-base meningiomas treated by a new approach with high-precision fractionated stereotactic radiotherapy. PATIENTS AND METHODS: One hundred eighty-nine patients with benign meningiomas were treated with conformal fractionated stereotactic radiotherapy between 1985 and 1998. Patients were undergoing a course of radiotherapy either as primary treatment, following subtotal resection, or for recurrent disease. The median target volume was 52.5 mL (range, 5.2 to 370 mL). The mean radiation dose was 56.8 Gy (± 4.4 Gy). Follow-up examinations, including magnetic resonance imaging, were performed at 6-month intervals thereafter. RESULTS: The median follow-up period was 35 months (range, 3 months to 12 years). Overall actuarial survival for patients with World Health Organization (WHO) grade I meningiomas was 97% after 5 years and 96% after 10 years. Local tumor failure was observed in three of 180 patients with WHO grade I tumors and was significantly higher in two of nine patients with WHO grade II tumors. A volume reduction of more than 50% was observed in 26 patients (14%). Preexisting cranial nerve symptoms resolved completely in 28% of the patients. Clinically significant treatment-induced toxicity was seen in 1.6% of the patients. No treatment-related deaths occurred. CONCLUSION: The results of this study demonstrate that fractionated stereotactic radiotherapy is safe and effective in the therapy of subtotally resected or unresectable meningiomas. The overall morbidity and incidence subacute and late side effects of this conformal radiotherapy approach were low.

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