Significant increase of high-risk chromosome 1q gain and 6q loss at recurrence in posterior fossa group A ependymoma: a multicenter study
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE226961 | GEO | 2023/05/31
REPOSITORIES: GEO
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Project description:Significant increase of high-risk chromosome 1q gain and 6q loss at recurrence in posterior fossa group A ependymoma: a multicenter study
| PRJNA942437 | ENA
Project description:Ependymoma (EPN) posterior fossa group A (PFA) has the highest rate of recurrence and the worst prognosis of all EPN types. At relapse, it is typically incurable even with re-resection and re-irradiation. The biology of recurrent PFA EPN remains largely unknown, which hinders clinical advances. In this large longitudinal multicenter study, we examined matched samples of primary and recurrent disease from PFA EPN patients (n=95) to investigate the biology of recurrence. DNA methylomic data was used to measure copy number variants (CNVs), revealing progressive large scale chromosome gains and losses in successive recurrences. These CNV changes were dominated by chromosome 1q gain and/or 6q loss (1q+/6q-), both previously identified as high-risk factors in PFA EPN, which were present in ~20% at presentation but increased to ~60% at 1st recurrence. These CNV changes were correlated with hypomethylation of heterochromatin associated DNA at presentation. Evolution of chromosomal aberrations was further explored using CNV analysis of single-nuclei RNAseq on approximately 46,000 PFA EPN cells from 6 matched pairs of primary and 1st relapse tumors that harbored CNV changes at recurrence. No evidence of rare subclones in primary tumors was observed, suggesting that chromosomal rearrangement events occur after initial presentation. Cellular and molecular characteristics associated with CNVs were examined by single-nuclei RNAseq, bulk transcriptomic analysis and immunohistochemistry, revealing that 1q+/6q- PFA have a significantly higher mitotic index, increased proportions of proliferative epithelial progenitors and decreased differentiated neoplastic subpopulations. Multivariate survival analyses showed that cases with 1q gain or 6q loss at 1st recurrence were significantly more likely to recur than cases with no 1q or 6q change. The high prevalence of 1q+/6q- at recurrence and the associated shortened survival, suggest that both these abnormalities should be routinely tested for, and used for trial stratification.
2023-06-01 | GSE227644 | GEO
Project description:Ependymoma (EPN) is a common brain tumor of childhood that, despite standard surgery and radiation therapy, has a relapse rate of 50%. Clinical trials have been unsuccessful in improving outcome by addition of chemotherapy, and identification of novel therapeutics has been hampered by a lack of in vitro and in vivo models. We describe 2 unique EPN cell lines (811 and 928) derived from recurrent intracranial metastases. Both cell lines harbor the high-risk chromosome 1q gain (1q+) and a derivative chromosome 6, and both are classified as molecular group A according to transcriptomic analysis. Transcriptional enrichment of extracellular matrix-related genes was a common signature of corresponding primary tumors and cell lines in both monolayer and 3D formats. EPN cell lines, when cultured in 3D format, clustered closer to the primary tumors with better fidelity of EPN-specific transcripts than when grown as a monolayer. Additionally, 3D culture revealed ependymal rosette formation and cilia-related ontologies, similar to in situ tumors. Our data confirm the validity of the 811 and 928 cell lines as representative models of intracranial, posterior fossa 1q+?EPN, which holds potential to advance translational science for patients affected by this tumor.
| S-EPMC5868094 | biostudies-literature
Project description:Two distinct groups of posterior fossa ependymoma, PF-EPN-A and PF-EPN-B have been identified in children and are often associated with widely distinct outcomes. We have identified an ultra-high-risk PF-EPN-A ependymoma with 6q loss. We performed RNA sequencing of posterior fossa ependymoma A (PF-EPN-A) tumor samples with chromosome 6q loss and balanced to understand the differences in 6q loss at the transcriptomic level
2021-02-15 | GSE164292 | GEO
Project description:BackgroundTreatment for pediatric posterior fossa group A (PFA) ependymoma with gain of chromosome 1q (1q+) has not improved over the past decade owing partially to lack of clinically relevant models. We described the first 2 1q+ PFA cell lines, which have significantly enhanced our understanding of PFA tumor biology and provided a tool to identify specific 1q+ PFA therapies. However, cell lines do not accurately replicate the tumor microenvironment. Our present goal is to establish patient-derived xenograft (PDX) mouse models.MethodsDisaggregated tumors from 2 1q+ PFA patients were injected into the flanks of NSG mice. Flank tumors were then transplanted into the fourth ventricle or lateral ventricle of NSG mice. Characterization of intracranial tumors was performed using imaging, histology, and bioinformatics.ResultsMAF-811_XC and MAF-928_XC established intracranially within the fourth ventricle and retained histological, methylomic, and transcriptomic features of primary patient tumors. We tested the feasibility of treating PDX mice with fractionated radiation or chemotherapy. Mice tolerated radiation despite significant tumor burden, and follow-up imaging confirmed radiation can reduce tumor size. Treatment with fluorouracil reduced tumor size but did not appear to prolong survival.ConclusionsMAF-811_XC and MAF-928_XC are novel, authentic, and reliable models for studying 1q+ PFA in vivo. Given the successful response to radiation, these models will be advantageous for testing clinically relevant combination therapies to develop future clinical trials for this high-risk subgroup of pediatric ependymoma.
| S-EPMC6917412 | biostudies-literature
Project description:Introduction: Ependymoma (EPN) studies have revealed certain genetic markers, such as gain of chromosome 1q (1q+), as indicators of poor survival and high rate of recurrence. Development of novel therapeutics for EPN has been hampered by a lack of in vivo and in vivo models. We describe two unique 1q+ cell lines (811 and 928) derived from two children with metastatic, recurrent EPN. Both cell lines were characterized using histological, karyotypic and transcriptomic methods Transcriptomic analysis revealed that both lines, when cultured in 3D format, clustered closer to primary EPN tumors than monolayer format and with better fidelity of EPN-specific transcripts, namely those related to cilia function. Additionally, 3D culture histology revealed striking ependymal rosette formation, similar to primary tumors. Transcriptional enrichment of extracellular matrix, however, was a common signature of EPN primary tumor and cell lines in both monolayer and 3D formats.
2016-09-09 | GSE86574 | GEO
Project description:RNA sequencing of posterior fossa ependymoma harboring 6q loss
| PRJNA689810 | ENA
Project description:BackgroundEpendymomas account for up to 10% of childhood CNS tumors and have a high rate of tumor recurrence despite gross total resection. Recently, classification into molecular ependymoma subgroups has been established, but the mechanisms underlying the aggressiveness of certain subtypes remain widely enigmatic. The aim of this study was to dissect the clinical and biological role of telomerase reactivation, a frequent mechanism of cancer cells to evade cellular senescence, in pediatric ependymoma.MethodsWe determined telomerase enzymatic activity, hTERT mRNA expression, promoter methylation, and the rs2853669 single nucleotide polymorphism located in the hTERT promoter in a well-characterized cohort of pediatric intracranial ependymomas.ResultsIn posterior fossa ependymoma group A (PF-EPN-A) tumors, telomerase activity varied and was significantly associated with dismal overall survival, whereas telomerase reactivation was present in all supratentorial RelA fusion-positive (ST-EPN-RELA) ependymomas. In silico analysis of methylation patterns showed that only these two subgroups harbor hypermethylated hTERT promoters suggesting telomerase reactivation via epigenetic mechanisms. Furthermore, chromosome 1q gain, a well-known negative prognostic factor, was strongly associated with telomerase reactivation in PF-EPN-A. Additional in silico analyses of gene expression data confirmed this finding and further showed enrichment of the E-twenty-six factor, Myc, and E2F target genes in 1q gained ependymomas. Additionally, 1q gained tumors showed elevated expression of ETV3, an E-twenty-six factor gene located on chromosome 1q.ConclusionTaken together we describe a subgroup-specific impact of telomerase reactivation on disease progression in pediatric ependymoma and provide preliminary evidence for the involved molecular mechanisms.
| S-EPMC5570194 | biostudies-literature
Project description:Genomewide DNA methylation array profiling of nine posterior fossa ependymomas harboring activating mutations in ACVR1. Two samples clustered with the PFA subtype and demonstrated H3K27me3 loss by immunohistochemistry, while the remaining 7 showed retained H3K27me3 and formed a methylation cluster distinct from other ependymal tumors. For these previsouly unpublished cases, the Illumina Infinium EPIC 850k Human DNA Methylation Beadchip was used to obtain DNA methylation profiles across approximately 850,000 CpG sites of genomic DNA extracted from formalin-fixed, paraffin-embedded tumor tissue.
2022-05-01 | GSE196013 | GEO
Project description:BACKGROUND:5-Hydroxymethylcytosine (5hmC) is a novel epigenetic mark and may be involved in the mechanisms of tumorigenesis and malignant transformation. However, the role of 5hmC in ependymoma, the third most common brain tumor in children, remains unclear. The aim of this study sought to identify the characterization of 5hmC levels in pediatric posterior fossa ependymoma and to evaluate whether 5hmC levels could be a potential factor to predict clinical outcomes. RESULTS:Our results showed that 5hmC levels were globally decreased in posterior fossa ependymoma compared with normal cerebellum tissues (P < 0.001). Group A posterior fossa ependymomas had higher 5hmC levels than group B tumors (P = 0.007). Moreover, 5hmC levels positively correlated with Ki-67 index in posterior fossa ependymoma (r = 0.428, P = 0.003). Multivariate Cox hazards model revealed that patients with high 5hmC levels (>?0.102%) had worse PFS and OS than patients with lower 5hmC levels (<?0.102%) (PFS: HR = 3.014; 95% CI, 1.040-8.738; P = 0.042; OS: HR = 2.788; 95% CI, 0.974-7.982; P = 0.047). CONCLUSIONS:Our findings suggest that loss of 5hmC is an epigenetic hallmark for pediatric posterior fossa ependymoma. 5hmC levels may represent a potential biomarker to predict prognosis in children with posterior fossa ependymoma.
| S-EPMC6988368 | biostudies-literature