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Neuro-oncology Nov 2020Ependymoma is a histologically defined central nervous system tumor most commonly occurring in childhood. Population-level incidence differences by race/ethnicity are...
BACKGROUND
Ependymoma is a histologically defined central nervous system tumor most commonly occurring in childhood. Population-level incidence differences by race/ethnicity are observed, with individuals of European ancestry at highest risk. We aimed to determine whether extent of European genetic ancestry is associated with ependymoma risk in US populations.
METHODS
In a multi-ethnic study of Californian children (327 cases, 1970 controls), we estimated the proportions of European, African, and Native American ancestry among recently admixed Hispanic and African American subjects and estimated European admixture among non-Hispanic white subjects using genome-wide data. We tested whether genome-wide ancestry differences were associated with ependymoma risk and performed admixture mapping to identify associations with local ancestry. We also evaluated race/ethnicity-stratified ependymoma incidence data from the Central Brain Tumor Registry of the United States (CBTRUS).
RESULTS
CBTRUS data revealed that African American and Native American children have 33% and 36%, respectively, reduced incidence of ependymoma compared with non-Hispanic whites. In genetic analyses, a 20% increase in European ancestry was associated with a 1.31-fold higher odds of ependymoma among self-reported Hispanics and African Americans (95% CI: 1.08-1.59, Pmeta = 6.7 × 10-3). Additionally, eastern European ancestral substructure was associated with increased ependymoma risk in non-Hispanic whites (P = 0.030) and in Hispanics (P = 0.043). Admixture mapping revealed a peak at 20p13 associated with increased local European ancestry, and targeted fine-mapping identified a lead variant at rs6039499 near RSPO4 (odds ratio = 1.99; 95% CI: 1.45-2.73; P = 2.2 × 10-5) but which was not validated in an independent set of posterior fossa type A patients.
CONCLUSIONS
Interethnic differences in ependymoma risk are recapitulated in the genomic ancestry of ependymoma patients, implicating regions to target in future association studies.
Topics: Black or African American; Child; Ependymoma; Female; Hispanic or Latino; Humans; Male; United States; White People
PubMed: 32607579
DOI: 10.1093/neuonc/noaa130 -
Acta Neuropathologica Dec 2019Spinal ependymal tumors form a histologically and molecularly heterogeneous group of tumors with generally good prognosis. However, their treatment can be challenging if...
Spinal ependymal tumors form a histologically and molecularly heterogeneous group of tumors with generally good prognosis. However, their treatment can be challenging if infiltration of the spinal cord or dissemination throughout the central nervous system (CNS) occurs and, in these cases, clinical outcome remains poor. Here, we describe a new and relatively rare subgroup of spinal ependymal tumors identified using DNA methylation profiling that is distinct from other molecular subgroups of ependymoma. Copy number variation plots derived from DNA methylation arrays showed MYCN amplification as a characteristic genetic alteration in all cases of our cohort (n = 13), which was subsequently validated using fluorescence in situ hybridization. The histological diagnosis was anaplastic ependymoma (WHO Grade III) in ten cases and classic ependymoma (WHO Grade II) in three cases. Histological re-evaluation in five primary tumors and seven relapses showed characteristic histological features of ependymoma, namely pseudorosettes, GFAP- and EMA positivity. Electron microscopy revealed cilia, complex intercellular junctions and intermediate filaments in a representative sample. Taking these findings into account, we suggest to designate this molecular subgroup spinal ependymoma with MYCN amplification, SP-EPN-MYCN. SP-EPN-MYCN tumors showed distinct growth patterns with intradural, extramedullary localization mostly within the thoracic and cervical spine, diffuse leptomeningeal spread throughout the whole CNS and infiltrative invasion of the spinal cord. Dissemination was observed in 100% of cases. Despite high-intensity treatment, SP-EPN-MYCN showed significantly worse median progression free survival (PFS) (17 months) and median overall survival (OS) (87 months) than all other previously described molecular spinal ependymoma subgroups. OS and PFS were similar to supratentorial ependymoma with RELA-fusion (ST-EPN-RELA) and posterior fossa ependymoma A (PF-EPN-A), further highlighting the aggressiveness of this distinct new subgroup. We, therefore, propose to establish SP-EPN-MYCN as a new molecular subgroup in ependymoma and advocate for testing newly diagnosed spinal ependymal tumors for MYCN amplification.
Topics: Adult; Brain Neoplasms; DNA Copy Number Variations; Ependymoma; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Mutation; N-Myc Proto-Oncogene Protein; Spinal Neoplasms
PubMed: 31414211
DOI: 10.1007/s00401-019-02056-2 -
F1000Research 2019Ependymomas are glial tumors derived from differentiated ependymal cells. In contrast to other types of brain tumors, histological grading is not a good prognostic...
Ependymomas are glial tumors derived from differentiated ependymal cells. In contrast to other types of brain tumors, histological grading is not a good prognostic marker for these tumors. In order to determine genomic changes in an anaplastic ependymoma, we analyzed its mutation patterns by next generation sequencing (NGS). Tumor DNA was sequenced using an Ion PI v3 chip on Ion Proton instrument and the data were analyzed by Ion Reporter 5.6. NGS analysis identified 19 variants, of which four were previously reported missense variants; c.395G>A in , c.1173A>G in , c.1416A>T in and c.215C>G in . The frequencies of the three missense mutations ( c.1173A>G, c.1416A>T, , c.215C>G) were high, suggesting that these are germline variants, whereas the variant frequency was low (4.81%). However, based on its FATHMM score of 0.94, only the variant is pathogenic; other variants , and had FATHMM scores of 0.22, 0.56 and 0.07, respectively. Eight synonymous mutations were found in , , , , , , and genes. The mutation in p.(Val592Val) was the only novel variant found. Additionally, two known intronic variants in were found and intronic variants were also found in and . A known splice site mutation at an acceptor site in , a 3'-UTR variant in the gene and a 5'_UTR variant in the gene were also identified. The p-values were below 0.00001 for all variants and the average coverage for all variants was around 2000x. In this grade III ependymoma, one novel synonymous mutation and one deleterious missense mutation is reported. Many of the variants reported here have not been detected in ependymal tumors by NGS analysis previously and we therefore report these variants in brain tissue for the first time.
Topics: Brain Neoplasms; DNA Mutational Analysis; Ependymoma; High-Throughput Nucleotide Sequencing; Humans; Mutation
PubMed: 32612806
DOI: 10.12688/f1000research.18721.2 -
Journal of Neuro-oncology Jul 2016Spinal cord ependymoma (SCE) is a rare tumor that is most commonly low-grade. Complete surgical resection has been established as first-line treatment and can be... (Review)
Review
Spinal cord ependymoma (SCE) is a rare tumor that is most commonly low-grade. Complete surgical resection has been established as first-line treatment and can be curative. However, SCEs tend to recur when complete tumor resection is not possible. Evidence supporting the use of adjuvant radiation and chemotherapy is not definitive. We review the most recent literature on SCE covering a comprehensive range of topics spanning the biology, presentation, clinical management, and outcomes. In addition, we present a case series of ten SCE patients with the goal of contributing to existing knowledge of this rare disease.
Topics: Adult; Cohort Studies; Ependymoma; Female; Follow-Up Studies; Humans; Male; Middle Aged; Spinal Cord; Spinal Cord Neoplasms; Young Adult
PubMed: 27154165
DOI: 10.1007/s11060-016-2135-8 -
International Journal of Radiation... Mar 2013Ependymoma is less commonly found in the supratentorial brain and has known clinical and molecular features that are unique. Our single-institution series provides...
PURPOSE
Ependymoma is less commonly found in the supratentorial brain and has known clinical and molecular features that are unique. Our single-institution series provides valuable information about disease control for supratentorial ependymoma and the complications of supratentorial irradiation in children.
METHODS AND MATERIALS
A total of 50 children with newly diagnosed supratentorial ependymoma were treated with adjuvant radiation therapy (RT); conformal methods were used in 36 after 1996. The median age at RT was 6.5 years (range, 1-18.9 years). The entire group was characterized according to sex (girls 27), race (white 43), extent of resection (gross-total 46), and tumor grade (anaplastic 28). The conformal RT group was prospectively evaluated for neurologic, endocrine, and cognitive effects.
RESULTS
With a median follow-up time of 9.1 years from the start of RT for survivors (range, 0.2-23.2 years), the 10-year progression-free and overall survival were 73% + 7% and 76% + 6%, respectively. None of the evaluated factors was prognostic for disease control. Local and distant failures were evenly divided among the 16 patients who experienced progression. Eleven patients died of disease, and 1 of central nervous system necrosis. Seizure disorders were present in 17 patients, and 4 were considered to be clinically disabled. Clinically significant cognitive effects were limited to children with difficult-to-control seizures. The average values for intelligence quotient and academic achievement (reading, spelling, and math) were within the range of normal through 10 years of follow-up. Central hypothyroidism was the most commonly treated endocrinopathy.
CONCLUSION
RT may be administered with acceptable risks for complications in children with supratentorial ependymoma. These results suggest that outcomes for these children are improving and that complications may be limited by use of focal irradiation methods.
Topics: Adolescent; Brain Neoplasms; Child; Child, Preschool; Cognition; Educational Status; Ependymoma; Female; Hormone Replacement Therapy; Humans; Infant; Intelligence; Male; Radiotherapy Dosage; Radiotherapy, Adjuvant; Radiotherapy, Conformal; Seizures; Supratentorial Neoplasms; Treatment Outcome; Young Adult
PubMed: 23245280
DOI: 10.1016/j.ijrobp.2012.10.033 -
Journal of Clinical Pathology Nov 2022An ependymoma shows divergent morphological and molecular features depending on their location. The paired box 6 () transcription factor is a putative tumour suppressor...
AIMS
An ependymoma shows divergent morphological and molecular features depending on their location. The paired box 6 () transcription factor is a putative tumour suppressor and drives cancer cells towards a stem cell-like state. A transcriptome study reported high expression in ependymal tumours, but data on protein expression are lacking.
METHODS
We, therefore, analysed expression by immunohistochemistry in 172 ependymoma samples and correlated its expression to histology, WHO grade, anatomical location and molecular subgroups.
RESULTS
Mean nuclear expression in ependymoma was 27.5% (95% CI 23.3 to 31.7). expression in subependymoma (mean: 5%) was significantly lower compared with myxopapillary (30%), WHO grade II (26%) and anaplastic ependymoma (35%). Supratentorial ependymomas also displayed significant lower levels (15%) compared with spinal cord tumours (30%). Expression levels in YAP1-fused ependymoma (41%) were higher compared with REL-associated protein (RELA)-fusion positive tumours (17%), while expression was similar in posterior fossa group A (33%) and B (29%) ependymomas. Kaplan-Meier analysis in RELA-fusion positive ependymomas and posterior fossa group B showed a significant better outcome for at or above the cut-off of 19.45% compared with tumours with below the cut-off.
CONCLUSIONS
We demonstrate that is frequently expressed in human ependymal tumours and immunohistochemistry may be helpful in determining prognostic relevant subgroups.
Topics: Humans; Prognosis; Ependymoma; Immunohistochemistry; Transcription Factors; Brain Neoplasms; PAX6 Transcription Factor
PubMed: 34183436
DOI: 10.1136/jclinpath-2021-207526 -
Chinese Journal of Cancer Nov 2016Posterior fossa ependymoma comprises two distinct molecular entities, ependymoma_posterior fossa A (EPN_PFA) and ependymoma_posterior fossa B (EPN_PFB), with...
Posterior fossa ependymoma comprises two distinct molecular entities, ependymoma_posterior fossa A (EPN_PFA) and ependymoma_posterior fossa B (EPN_PFB), with differentiable gene expression profiles. As yet, the response of the two entities to treatment is unclear. To determine the relationship between the two molecular subgroups of posterior fossa ependymoma and treatment, we studied a cohort of 820 patients with molecularly profiled, clinically annotated posterior fossa ependymomas. We found that the strongest predictor of poor outcome in patients with posterior fossa ependymoma across the entire age spectrum was molecular subgroup EPN_PFA, which was recently reported in the paper entitled "Therapeutic impact of cytoreductive surgery and irradiation of posterior fossa ependymoma in the molecular era: a retrospective multicohort analysis" in the Journal of Clinical Oncology. Patients with incompletely resected EPN_PFA tumors had a very poor outcome despite receiving adjuvant radiation therapy, whereas a substantial proportion of patients with EPN_PFB tumors can be cured with surgery alone.
Topics: Cranial Fossa, Posterior; Ependymoma; Humans
PubMed: 27846874
DOI: 10.1186/s40880-016-0155-6 -
Brain Tumor Pathology Apr 2014We report the case of a 61-year-old man with supratentorial extraventricular anaplastic ependymoma who presented with repeated intratumoral hemorrhage. The patient was... (Review)
Review
We report the case of a 61-year-old man with supratentorial extraventricular anaplastic ependymoma who presented with repeated intratumoral hemorrhage. The patient was admitted with headache. Computed tomography and magnetic resonance imaging showed an enhancing mass with intratumoral hemorrhage in the right temporal lobe. Gross total resection was performed. The tumor was well demarcated from the brain tissue, and showed no continuity with the ventricular system. Histopathological examination revealed the features of anaplastic ependymoma. Therefore, additional radiation therapy and adjuvant chemotherapy were administered. Ten months later, the tumor recurred with hemorrhage in the spinal canal. This case showed rapid malignant progression and repeated intratumoral hemorrhage within a short period of time, both of which are characteristics of anaplastic ependymomas. Close observation of the central nervous system and adjuvant radiotherapy are mandatory, even if the ependymoma presents with repeated intratumoral hemorrhage.
Topics: Brain; Carotid Artery, Internal; Cerebral Angiography; Cerebral Hemorrhage; Combined Modality Therapy; Ependymoma; Headache; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Recurrence; Supratentorial Neoplasms; Tomography, X-Ray Computed
PubMed: 23546851
DOI: 10.1007/s10014-013-0146-0 -
Nature Communications Apr 2024Central nervous system (CNS) tumors are the leading cause of pediatric cancer death, and these patients have an increased risk for developing secondary neoplasms. Due to...
Central nervous system (CNS) tumors are the leading cause of pediatric cancer death, and these patients have an increased risk for developing secondary neoplasms. Due to the low prevalence of pediatric CNS tumors, major advances in targeted therapies have been lagging compared to other adult tumors. We collect single nuclei RNA-seq data from 84,700 nuclei of 35 pediatric CNS tumors and three non-tumoral pediatric brain tissues and characterize tumor heterogeneity and transcriptomic alterations. We distinguish cell subpopulations associated with specific tumor types including radial glial cells in ependymomas and oligodendrocyte precursor cells in astrocytomas. In tumors, we observe pathways important in neural stem cell-like populations, a cell type previously associated with therapy resistance. Lastly, we identify transcriptomic alterations among pediatric CNS tumor types compared to non-tumor tissues, while accounting for cell type effects on gene expression. Our results suggest potential tumor type and cell type-specific targets for pediatric CNS tumor treatment. Here we address current gaps in understanding single nuclei gene expression profiles of previously under-investigated tumor types and enhance current knowledge of gene expression profiles of single cells of various pediatric CNS tumors.
Topics: Humans; Child; Central Nervous System Neoplasms; Gene Expression Regulation, Neoplastic; Ependymoma; Transcriptome; Child, Preschool; Astrocytoma; Gene Expression Profiling; Female; RNA-Seq; Male; Adolescent; Neural Stem Cells; Cell Nucleus
PubMed: 38688897
DOI: 10.1038/s41467-024-47712-8 -
Brain Tumor Pathology Jul 2023EPN-ZFTA is a rare brain tumor where prognostic factors remain unclear and no effective immunotherapy or chemotherapy is currently available. Therefore, this study...
A clinicopathological analysis of supratentorial ependymoma, ZFTA fusion-positive: utility of immunohistochemical detection of CDKN2A alterations and characteristics of the immune microenvironment.
EPN-ZFTA is a rare brain tumor where prognostic factors remain unclear and no effective immunotherapy or chemotherapy is currently available. Therefore, this study investigated its clinicopathological features, evaluated the utility of MTAP and p16 IHC as surrogate markers of CDKN2A alterations, and characterized the immune microenvironment of EPN-ZFTA. Thirty surgically removed brain tumors, including 10 EPN-ZFTA, were subjected to IHC. MLPA was performed for CDKN2A HD in 20 ependymal tumors, including EPN-ZFTA. The 5-years OS and PFS of EPN-ZFTA were 90% and 60%, respectively. CDKN2A HD was detected in two cases of EPN-ZFTA; these cases were immunohistochemically negative for both MTAP and p16 and recurred earlier after surgery. As for the immune microenvironment of EPN-ZFTA, B7-H3, but not PD-L1, was positive in all cases of EPN-ZFTA; Iba-1-positive or CD204-positive macrophages were large, while infiltrating lymphocytes were small, in number in EPN-ZFTA. Collectively, these results indicate the potential of MTAP and p16 IHC as useful surrogate markers of CDKN2A HD in EPN-ZFTA, and tumor-associated macrophages, including the M2 type, may contribute to its immune microenvironment. Furthermore, the expression of B7-H3 in EPN-ZFTA may indicate the usefulness of B7-H3 as a target of immune checkpoint chemotherapy for EPN-ZFTA via B7-H3 pathway.
Topics: Humans; Cyclin-Dependent Kinase Inhibitor p16; Ependymoma; Brain Neoplasms; Tumor Microenvironment
PubMed: 37322295
DOI: 10.1007/s10014-023-00464-7