Intracranial ependymomas: molecular insights and translation to treatment.
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ABSTRACT:
SUBMITTER: Lester A
PROVIDER: S-EPMC8018002 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Ependymomas are neoplasms that can occur anywhere along the craniospinal axis. They are the third most common brain tumor in children, representing 10% of pediatric intracranial tumors, 4% of adult brain tumors, and 15% of all spinal cord tumors. As the heterogeneity of ependymomas has severely limited the prognostic value of the World Health Organization grading system, numerous studies have focused on genetic alterations as a potential basis for classification and prognosis. However, this endeavor has proven difficult due to variations of findings depending on tumor location, tumor grade, and patient age. While many have evaluated chromosomal abnormalities for ependymomas as a whole group, others have concentrated their efforts on specific subsets of populations. Here, we review modern findings of chromosomal analyses, their relationships with various genes, and their prognostic implications for intracranial and spinal cord ependymomas.
| S-EPMC3615711 | biostudies-literature
Project description:BackgroundPrimary intracranial ependymomas (IE) are rare brain tumors rarely metastasizing outside the central nervous system. We systematically reviewed the literature on extra-neural metastases from primary IEs.MethodsPubMed, Scopus, Web-of-Science, and Cochrane were searched following the PRISMA guidelines to include studies of extra-neural metastases from primary IEs. Clinical features, management strategies, and survival were analyzed.ResultsWe collected 48 patients from 43 studies. Median age was 13 years (range, 2-65). Primary IEs were frequently located in the parietal (22.9%) and frontal (16.7%) lobes, and mostly treated with resection (95.8%) and/or radiotherapy (62.5%). Most IEs were of grade-III (79.1%), and few of grade-I (6.3%) or grade-II (14.6%). 45 patients experienced intracranial recurrences, mostly treated with resection (86.7%), radiotherapy (60%), and/or chemotherapy (24.4%). Median time-interval from primary IEs was 28 months (range, 0-140). Most extra-neural metastases were diagnosed at imaging (37.5%) or autopsy (35.4%). Extra-neural metastases were multifocal in 38 patients (79.1%), mostly involving cervical or hilar lymph-nodes (66.7%), lung/pleura (47.9%), and/or scalp (29.1%). Surgical resection (31.3%), chemotherapy (31.3%) and locoregional radiotherapy (18.8%) were the most common treatments for extra-neural metastases, but 28 (58.3%) patients were not treated. At last follow-up, 37 patients died with median overall-survivals from primary IEs of 36 months (range, 1-239), and from extra-neural metastases of 3 months (range, 0.1-36). Overall-survival was significantly longer in patients with grade-I and II IEs (P=0.040).ConclusionExtra-neural metastases from primary IEs are rare, but mostly occur at later disease stages. Multidisciplinary management strategies should be intended mostly for palliation.
| S-EPMC9093681 | biostudies-literature
Project description:Simple Summary The current trend in neuropathology directs to the integrated histo-molecular approach. The traditional concept of histological grade should be complemented by comprehensive diagnostics with the mandatory use of molecular genetic markers. As a consequence, basic types of CNS tumors fall into multiple nosological entities that can be morphologically similar while having fundamentally different pathogenesis and clinical presentation. This trend is particularly evident for ependymal tumors, which harbor molecular markers of decisive importance for the prognosis. This minireview emphasizes recent achievements in ependymoma biology research closely connected with state-of-the-art diagnostics. Abstract Ependymomas are among the most enigmatic tumors of the central nervous system, posing enormous challenges for pathologists and clinicians. Despite the efforts made, the treatment options are still limited to surgical resection and radiation therapy, while none of conventional chemotherapies is beneficial. While being histologically similar, ependymomas show considerable clinical and molecular diversity. Their histopathological evaluation alone is not sufficient for reliable diagnostics, prognosis, and choice of treatment strategy. The importance of integrated diagnosis for ependymomas is underscored in the recommendations of Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy. These updated recommendations were adopted and implemented by WHO experts. This minireview highlights recent advances in comprehensive molecular-genetic characterization of ependymomas. Strong emphasis is made on the use of molecular approaches for verification and specification of histological diagnoses, as well as identification of prognostic markers for ependymomas in children.
| S-EPMC8507860 | biostudies-literature
Project description:Extensive molecular analyses of ependymal tumors have revealed that supratentorial and posterior fossa ependymomas have distinct molecular profiles and are likely to be different diseases. The presence of C11orf95-RELA fusion genes in a subset of supratentorial ependymomas (ST-EPN) indicated the existence of molecular subgroups. However, the pathogenesis of RELA fusion-negative ependymomas remains elusive. To investigate the molecular pathogenesis of these tumors and validate the molecular classification of ependymal tumors, we conducted thorough molecular analyses of 113 locally diagnosed ependymal tumors from 107 patients in the Japan Pediatric Molecular Neuro-Oncology Group. All tumors were histopathologically reviewed and 12 tumors were re-classified as non-ependymomas. A combination of RT-PCR, FISH, and RNA sequencing identified RELA fusion in 19 of 29 histologically verified ST-EPN cases, whereas another case was diagnosed as ependymoma RELA fusion-positive via the methylation classifier (68.9%). Among the 9 RELA fusion-negative ST-EPN cases, either the YAP1 fusion, BCOR tandem duplication, EP300-BCORL1 fusion, or FOXO1-STK24 fusion was detected in single cases. Methylation classification did not identify a consistent molecular class within this group. Genome-wide methylation profiling successfully sub-classified posterior fossa ependymoma (PF-EPN) into PF-EPN-A (PFA) and PF-EPN-B (PFB). A multivariate analysis using Cox regression confirmed that PFA was the sole molecular marker which was independently associated with patient survival. A clinically applicable pyrosequencing assay was developed to determine the PFB subgroup with 100% specificity using the methylation status of 3 genes, CRIP1, DRD4 and LBX2. Our results emphasized the significance of molecular classification in the diagnosis of ependymomas. RELA fusion-negative ST-EPN appear to be a heterogeneous group of tumors that do not fall into any of the existing molecular subgroups and are unlikely to form a single category.
| S-EPMC6278135 | biostudies-literature
Project description:Ependymomas are glial tumors that originate in either intracranial or spinal regions. Although tumors from different regions are histologically similar, they are biologically distinct. We therefore sought to identify molecular characteristics of spinal ependymomas (SEPN) in order to better understand the disease biology of these tumors. Using gene expression profiles of 256 tumor samples, we identified increased expression of 1,866 genes in SEPN when compared to intracranial ependymomas. These genes are mainly related to anterior/posterior pattern specification, response to oxidative stress, glial cell differentiation, DNA repair, and PPAR signalling, and also significantly enriched with cellular senescence genes (P = 5.5 × 10-03). In addition, a high number of significantly down-regulated genes in SEPN are localized to chromosome 22 (81 genes from chr22: 43,325,255 - 135,720,974; FDR = 1.77 × 10-23 and 22 genes from chr22: 324,739 - 32,822,302; FDR = 2.07 × 10-09) including BRD1, EP300, HDAC10, HIRA, HIC2, MKL1, and NF2. Evaluation of NF2 co-expressed genes further confirms the enrichment of chromosome 22 regions. Finally, systematic integration of chromosome 22 genes with interactome and NF2 co-expression data identifies key candidate genes. Our results reveal unique molecular characteristics of SEPN such as altered expression of cellular senescence and chromosome 22 genes.
| S-EPMC4637320 | biostudies-literature
Project description: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 RELA fusion-positive ependymoma has been renamed into ZFTA fusion-positive and the novel YAP1 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 MYCN 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.
| S-EPMC9763977 | biostudies-literature
Project description:To assess the clinicopathological features and prognostic factors of pediatric intracranial ependymomas and to explore the current diagnostic practice, we analyzed clinical data from the Brain Tumor Registry of Japan (BTRJ). Data of fifty children under 18 years of age diagnosed with intracranial ependymoma were extracted from the BTRJ database. Cases were reviewed for overall survival (OS) and progression-free survival (PFS), with attention to gender, preoperative Karnofsky performance status score, location of the tumor, the extent of resection, World Health Organization (WHO) histopathological grading, and adjuvant therapy. The median age at diagnosis was 6.1 years, ranging from 7 months to 17.6 years. Based on the WHO histopathological grading, 27 patients were classified under grade 2 (54%) and 23 patients were classified under grade 3 (46%). Gross total resection (GTR) was achieved in 30 patients (60%). The median follow-up time was 65 months. Five-year PFS and OS were 47.2 ± 7.3% and 73.3 ± 6.7%, respectively. GTR was associated with longer OS (P = 0.02). The histopathological grading was not an independent prognostic factor for the OS. Mitosis and microvascular proliferation were higher among patients with grade 3 than in those with grade 2, which aided in deciding the WHO grade. This nationwide study revealed the characteristics and outcomes of patients with childhood ependymomas. GTR was the factor most consistently associated with improved survival. In contrast, the histopathological grading in this cohort was not a significant prognostic factor. More reproducible and practical criteria for the diagnosis of intracranial ependymomas should be further pursued in future studies.
| S-EPMC9357454 | biostudies-literature
Project description:IntroductionAtypical teratoid rhabdoid tumor (ATRT) is a rare, often lethal brain tumor of childhood characterized by a complex epigenetic landscape amongst a simple genetic background. Recent molecular studies have defined key biologic events that contribute to tumorigenesis and molecular subtypes of ATRT.MethodsSeminal studies on ATRT are reviewed with an emphasis on molecular pathogenesis and its relevance to novel therapeutics.ResultsIn this review, we summarize the key clinicopathologic and molecular features of ATRT, completed and ongoing clinical trials and outline the translational potential of novel insights into the molecular pathogenesis of this tumor.ConclusionsSMARCB1 loss is the key genetic event in ATRT pathogenesis that leads to widespread epigenetic dysregulation and loss of lineage-specific enhancers. Current work is defining subtype-specific treatments that target underlying molecular derangements that drive tumorigenesis.
| S-EPMC8230985 | biostudies-literature
Project description:Goal of the experiment : Recurrence is a frequent phenomenon in intracranial childhood ependymomas. To understand this process, we investigated whether the gene expression profiling of matched ependymomas at diagnosis and at relapse could reveal key molecular events involved in tumor progression. To gain new insight in this process and identify mechanisms associated with recurrence, we compared the CGH profiles of local recurrences with the corresponding initial tumors. Brief description We analyzed 17 tumor samples at diagnosis and a total of 27 paired recurrences. Recurrences analyzed occurred after surgery only in 12 cases, surgery plus chemotherapy only in 9 cases and any treatment plus radiotherapy in 6 cases. We compared the level of CGH profile for each tumor at diagnosis and recurrence relative to normal commercial DNA using Agilent 4x44K Human CGH microarrays.
2011-06-20 | E-TABM-1023 | biostudies-arrayexpress
Project description:Of nine ependymoma molecular groups detected by DNA methylation profiling, the posterior fossa type A (PFA) is most prevalent. We used DNA methylation profiling to look for further molecular heterogeneity among 675 PFA ependymomas. Two major subgroups, PFA-1 and PFA-2, and nine minor subtypes were discovered. Transcriptome profiling suggested a distinct histogenesis for PFA-1 and PFA-2, but their clinical parameters were similar. In contrast, PFA subtypes differed with respect to age at diagnosis, gender ratio, outcome, and frequencies of genetic alterations. One subtype, PFA-1c, was enriched for 1q gain and had a relatively poor outcome, while patients with PFA-2c ependymomas showed an overall survival at 5 years of >?90%. Unlike other ependymomas, PFA-2c tumors express high levels of OTX2, a potential biomarker for this ependymoma subtype with a good prognosis. We also discovered recurrent mutations among PFA ependymomas. H3 K27M mutations were present in 4.2%, occurring only in PFA-1 tumors, and missense mutations in an uncharacterized gene, CXorf67, were found in 9.4% of PFA ependymomas, but not in other groups. We detected high levels of wildtype or mutant CXorf67 expression in all PFA subtypes except PFA-1f, which is enriched for H3 K27M mutations. PFA ependymomas are characterized by lack of H3 K27 trimethylation (H3 K27-me3), and we tested the hypothesis that CXorf67 binds to PRC2 and can modulate levels of H3 K27-me3. Immunoprecipitation/mass spectrometry detected EZH2, SUZ12, and EED, core components of the PRC2 complex, bound to CXorf67 in the Daoy cell line, which shows high levels of CXorf67 and no expression of H3 K27-me3. Enforced reduction of CXorf67 in Daoy cells restored H3 K27-me3 levels, while enforced expression of CXorf67 in HEK293T and neural stem cells reduced H3 K27-me3 levels. Our data suggest that heterogeneity among PFA ependymomas could have clinicopathologic utility and that CXorf67 may have a functional role in these tumors.
| S-EPMC6105278 | biostudies-literature