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Current Oncology Reports Aug 2022To review state of art and relevant advances in the molecular genetics and management of ependymomas of children and adults. (Review)
Review
PURPOSE OF REVIEW
To review state of art and relevant advances in the molecular genetics and management of ependymomas of children and adults.
RECENT FINDINGS
Ependymomas may occur either in the brain or in the spinal cord. Compared with intracranial ependymomas, spinal ependymomas are less frequent and exhibit a better prognosis. The new WHO classification of CNS tumors of 2021 has subdivided ependymomas into different histomolecular subgroups with different outcome. The majority of studies have shown a major impact of extent of resection; thus, a complete resection must be performed, whenever possible, at first surgery or at reoperation. Conformal radiotherapy is recommended for grade 3 or incompletely resected grade II tumors. Proton therapy is increasingly employed especially in children to reduce the risk of neurocognitive and endocrine sequelae. Craniospinal irradiation is reserved for metastatic disease. Chemotherapy is not useful as primary treatment and is commonly employed as salvage treatment for patients failing surgery and radiotherapy. Standard treatments are still the mainstay of treatment: the discovery of new druggable pathways will hopefully increase the therapeutic armamentarium in the near future.
Topics: Adult; Brain Neoplasms; Child; Ependymoma; Humans; Prognosis; Salvage Therapy
PubMed: 35384591
DOI: 10.1007/s11912-022-01260-w -
Neuro-oncology Mar 2018Ependymal tumors are rare CNS tumors and may occur at any age, but their proportion among primary brain tumors is highest in children and young adults. Thus, the level... (Review)
Review
Ependymal tumors are rare CNS tumors and may occur at any age, but their proportion among primary brain tumors is highest in children and young adults. Thus, the level of evidence of diagnostic and therapeutic interventions is higher in the pediatric compared with the adult patient population.The diagnosis and disease staging is performed by craniospinal MRI. Tumor classification is achieved by histological and molecular diagnostic assessment of tissue specimens according to the World Health Organization (WHO) classification 2016. Surgery is the crucial initial treatment in both children and adults. In pediatric patients with intracranial ependymomas of WHO grades II or III, surgery is followed by local radiotherapy regardless of residual tumor volume. In adults, radiotherapy is employed in patients with anaplastic ependymoma WHO grade III, and in case of incomplete resection of WHO grade II ependymoma. Chemotherapy alone is reserved for young children <12 months and for adults with recurrent disease when further surgery and irradiation are no longer feasible. A gross total resection is the mainstay of treatment in spinal ependymomas, and radiotherapy is reserved for incompletely resected tumors. Nine subgroups of ependymal tumors across different anatomical compartments (supratentorial, posterior fossa, spinal) and patient ages have been identified with distinct genetic and epigenetic alterations, and with distinct outcomes. These findings may lead to more precise diagnostic and prognostic assessments, molecular subgroup-adapted therapies, and eventually new recommendations pending validation in prospective studies.
Topics: Ependymoma; Humans; Practice Guidelines as Topic; Prognosis
PubMed: 29194500
DOI: 10.1093/neuonc/nox166 -
Pathologica Dec 2022Ependymal neoplasms are a heterogenous group of neoplasms arising from the progenitors of the cells lining the ventricular system and the spinal central canal. During... (Review)
Review
Ependymal neoplasms are a heterogenous group of neoplasms arising from the progenitors of the cells lining the ventricular system and the spinal central canal. During the last few years, significant novel data concerning oncogenesis, molecular characteristics and clinical correlations of these tumours have been collected, with a strong relevance for their pathological classification. The recently published 5th edition of WHO Classification of Central Nervous System Tumours integrates this novel knowledge and represents a substantial update compared to the previous edition. Concerning supratentorial ependymomas, the previous fusion-positive ependymoma has been renamed into fusion-positive and the novel fusion-positive ependymoma subtype has been added. Posterior fossa ependymomas should now be allocated either to the Type A or Type B subtypes based on molecular profiling or using the H3 K27me3 immunohistochemical surrogate. Regarding spinal ependymomas, a novel subtype has been added based on a distinctive molecular trait, presence of amplification, and on the unfavourable outcome. Finally, myxopapillary ependymoma is now classified as a grade 2 tumour in accordance with its overall prognosis which mirrors that of conventional spinal ependymomas. The aim of this review is to present these changes and summarize the current diagnostic framework of ependymal tumours, according to the most recent updates.
Topics: Humans; Ependymoma; Prognosis
PubMed: 36534422
DOI: 10.32074/1591-951X-817 -
Journal of Clinical Oncology : Official... Apr 2019The Children's Oncology Group trial ACNS0121 estimated event-free survival (EFS) and overall survival for children with intracranial ependymoma treated with surgery,... (Clinical Trial)
Clinical Trial
Conformal Radiation Therapy for Pediatric Ependymoma, Chemotherapy for Incompletely Resected Ependymoma, and Observation for Completely Resected, Supratentorial Ependymoma.
PURPOSE
The Children's Oncology Group trial ACNS0121 estimated event-free survival (EFS) and overall survival for children with intracranial ependymoma treated with surgery, radiation therapy, and-selectively-with chemotherapy. Treatment was administered according to tumor location, histologic grade, and extent of resection. The impacts of histologic grade, focal copy number gain on chromosome 1q, and DNA methylation profiles were studied for those undergoing surgery and immediate postoperative conformal radiation therapy (CRT).
METHODS
ACNS0121 included 356 newly diagnosed patients (ages 1 to 21 years). Patients with classic supratentorial ependymoma were observed after gross total resection (GTR). Those undergoing subtotal resection received chemotherapy, second surgery, and CRT. The remaining patients received immediate postoperative CRT after near-total resection or GTR. CRT was administered with a 1.0-cm clinical target volume margin. The cumulative total dose was 59.4 Gy, except for patients who underwent GTR and were younger than age 18 months (who received 54 Gy). Patients were enrolled between October 2003 and September 2007 and were observed for 5 years. Supratentorial tumors were evaluated for fusion; infratentorial tumors, for chromosome 1q gain. Classification of posterior fossa groups A and B was made by methylation profiles.
RESULTS
The 5-year EFS rates were 61.4% (95% CI, 34.5% to 89.6%), 37.2% (95% CI, 24.8% to 49.6%), and 68.5% (95% CI, 62.8% to 74.2%) for observation, subtotal resection, and near-total resection/GTR groups given immediate postoperative CRT, respectively. The 5-year EFS rates differed significantly by tumor grade ( = .0044) but not by age, location, fusion status, or posterior fossa A/posterior fossa B grouping. EFS was higher for patients with infratentorial tumors without 1q gain than with 1q gain (82.8% [95% CI, 74.4% to 91.2%] 47.4% [95% CI, 26.0% to 68.8%]; = .0013).
CONCLUSION
The EFS for patients with ependymoma younger than 3 years of age who received immediate postoperative CRT and for older patients is similar. Irradiation should remain the mainstay of care for most subtypes.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Child; Child, Preschool; Cytoreduction Surgical Procedures; Ependymoma; Female; Humans; Infant; Male; Progression-Free Survival; Radiotherapy, Conformal; Supratentorial Neoplasms; Transcription Factor RelA; Treatment Outcome; Young Adult
PubMed: 30811284
DOI: 10.1200/JCO.18.01765 -
Cancer Cell Jul 2020Ependymoma is a heterogeneous entity of central nervous system tumors with well-established molecular groups. Here, we apply single-cell RNA sequencing to analyze...
Ependymoma is a heterogeneous entity of central nervous system tumors with well-established molecular groups. Here, we apply single-cell RNA sequencing to analyze ependymomas across molecular groups and anatomic locations to investigate their intratumoral heterogeneity and developmental origins. Ependymomas are composed of a cellular hierarchy initiating from undifferentiated populations, which undergo impaired differentiation toward three lineages of neuronal-glial fate specification. While prognostically favorable groups of ependymoma predominantly harbor differentiated cells, aggressive groups are enriched for undifferentiated cell populations. The delineated transcriptomic signatures correlate with patient survival and define molecular dependencies for targeted treatment approaches. Taken together, our analyses reveal a developmental hierarchy underlying ependymomas relevant to biological and clinical behavior.
Topics: Cell Differentiation; Cell Proliferation; Central Nervous System Neoplasms; Child; Ependymoma; Genomics; Humans; Neurons; Prognosis; Sequence Analysis, RNA; Single-Cell Analysis; Survival Analysis
PubMed: 32663469
DOI: 10.1016/j.ccell.2020.06.004 -
Cancer Cell May 2015Ependymal tumors across age groups are currently classified and graded solely by histopathology. It is, however, commonly accepted that this classification scheme has...
Ependymal tumors across age groups are currently classified and graded solely by histopathology. It is, however, commonly accepted that this classification scheme has limited clinical utility based on its lack of reproducibility in predicting patients' outcome. We aimed at establishing a uniform molecular classification using DNA methylation profiling. Nine molecular subgroups were identified in a large cohort of 500 tumors, 3 in each anatomical compartment of the CNS, spine, posterior fossa, supratentorial. Two supratentorial subgroups are characterized by prototypic fusion genes involving RELA and YAP1, respectively. Regarding clinical associations, the molecular classification proposed herein outperforms the current histopathological classification and thus might serve as a basis for the next World Health Organization classification of CNS tumors.
Topics: Adaptor Proteins, Signal Transducing; Adolescent; Adult; Age Factors; Aged; Central Nervous System Neoplasms; Child; Child, Preschool; DNA Methylation; Ependymoma; Female; Gene Dosage; Gene Expression Profiling; Gene Fusion; Humans; Infant; Male; Middle Aged; Phosphoproteins; Transcription Factors; Transcription, Genetic; YAP-Signaling Proteins; Young Adult
PubMed: 25965575
DOI: 10.1016/j.ccell.2015.04.002 -
Nature Communications Apr 2023Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial ZFTA-fusion associated and...
Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial ZFTA-fusion associated and the posterior fossa ependymoma group A. In both groups, tumors occur mainly in young children and frequently recur after treatment. Although molecular mechanisms underlying these diseases have recently been uncovered, they remain difficult to target and innovative therapeutic approaches are urgently needed. Here, we use genome-wide chromosome conformation capture (Hi-C), complemented with CTCF and H3K27ac ChIP-seq, as well as gene expression and DNA methylation analysis in primary and relapsed ependymoma tumors, to identify chromosomal conformations and regulatory mechanisms associated with aberrant gene expression. In particular, we observe the formation of new topologically associating domains ('neo-TADs') caused by structural variants, group-specific 3D chromatin loops, and the replacement of CTCF insulators by DNA hyper-methylation. Through inhibition experiments, we validate that genes implicated by these 3D genome conformations are essential for the survival of patient-derived ependymoma models in a group-specific manner. Thus, this study extends our ability to reveal tumor-dependency genes by 3D genome conformations even in tumors that lack targetable genetic alterations.
Topics: Child; Humans; Child, Preschool; Neoplasm Recurrence, Local; Chromosomes; Chromosome Mapping; Ependymoma; Genome; Chromatin
PubMed: 37085539
DOI: 10.1038/s41467-023-38044-0 -
Nature Neuroscience May 2023The spatiotemporal regulation of cell fate specification in the human developing spinal cord remains largely unknown. In this study, by performing integrated analysis of...
The spatiotemporal regulation of cell fate specification in the human developing spinal cord remains largely unknown. In this study, by performing integrated analysis of single-cell and spatial multi-omics data, we used 16 prenatal human samples to create a comprehensive developmental cell atlas of the spinal cord during post-conceptional weeks 5-12. This revealed how the cell fate commitment of neural progenitor cells and their spatial positioning are spatiotemporally regulated by specific gene sets. We identified unique events in human spinal cord development relative to rodents, including earlier quiescence of active neural stem cells, differential regulation of cell differentiation and distinct spatiotemporal genetic regulation of cell fate choices. In addition, by integrating our atlas with pediatric ependymomas data, we identified specific molecular signatures and lineage-specific genes of cancer stem cells during progression. Thus, we delineate spatiotemporal genetic regulation of human spinal cord development and leverage these data to gain disease insight.
Topics: Child; Female; Pregnancy; Humans; Spinal Cord; Ependymoma; Cell Differentiation; Neural Stem Cells; Gene Expression; Gene Expression Profiling; Gene Expression Regulation, Developmental
PubMed: 37095395
DOI: 10.1038/s41593-023-01312-9 -
Chinese Journal of Cancer Oct 2011Brain tumors are the leading cause of cancer death in children, with ependymoma being the third most common and posing a significant clinical burden. Its mechanism of... (Review)
Review
Brain tumors are the leading cause of cancer death in children, with ependymoma being the third most common and posing a significant clinical burden. Its mechanism of pathogenesis, reliable prognostic indicators, and effective treatments other than surgical resection have all remained elusive. Until recently, ependymoma research was hindered by the small number of tumors available for study, low resolution of cytogenetic techniques, and lack of cell lines and animal models. Ependymoma heterogeneity, which manifests as variations in tumor location, patient age, histological grade, and clinical behavior, together with the observation of a balanced genomic profile in up to 50% of cases, presents additional challenges in understanding the development and progression of this disease. Despite these difficulties, we have made significant headway in the past decade in identifying the genetic alterations and pathways involved in ependymoma tumorigenesis through collaborative efforts and the application of microarray-based genetic (copy number) and transcriptome profiling platforms. Genetic characterization of ependymoma unraveled distinct mRNA-defined subclasses and led to the identification of radial glial cells as its cell type of origin. This review summarizes our current knowledge in the molecular genetics of ependymoma and proposes future research directions necessary to further advance this field.
Topics: Adult; Animals; Brain Neoplasms; Cell Transformation, Neoplastic; Child, Preschool; Chromosome Aberrations; Ependymoma; Epigenesis, Genetic; Gene Expression Profiling; Humans; Neuroglia
PubMed: 21959044
DOI: 10.5732/cjc.011.10129 -
Journal of Neurosurgical Sciences Feb 2018Ependymomas are rare primary central nervous system tumors occurring in children and young adults. They can be indolent or locally aggressive depending on location,... (Review)
Review
Ependymomas are rare primary central nervous system tumors occurring in children and young adults. They can be indolent or locally aggressive depending on location, histology, and extent of resection. Treatment involves maximal surgical resection and usually focal radiation therapy, depending on the presence of residual disease and tumor grade. Chemotherapy has been studied for both adults and children but do not have an established role in adjuvant therapy. In both age groups, treatment with mainly cisplatin based regimens can be considered in the setting of residual disease after surgery or for salvage therapy when surgery or further radiation is not indicated. In children, chemotherapy can be considered in very young children to delay radiation or to increase the likelihood of complete resection in second look surgery. Targeted agents such as bevacizumab and lapatinib do not have a role in adjuvant therapy for ependymomas but are being explored for recurrent disease. This review discusses adjuvant therapy in both adult and child populations.
Topics: Adolescent; Antineoplastic Agents; Central Nervous System Neoplasms; Chemotherapy, Adjuvant; Child; Ependymoma; Female; Humans; Male; Young Adult
PubMed: 28945055
DOI: 10.23736/S0390-5616.17.04211-4