Single-cell ATAC-Seq of recurrent pediatric high-grade glioma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE163656 | GEO | 2021/10/20
REPOSITORIES: GEO
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Project description:We performed scATAC-seq on glioblastoma tissue samples taken at time of initial surgical resection to map the global chromatin profiles of glioblastoma cells and associated non-neoplastic cells
2021-10-20 | GSE163655 | GEO
Project description:We performed scATAC-seq on primary glioblastoma tissue samples taken at time of initial resection to map the global chromatin profiles of glioblastoma cells and associated non-neoplastic cells
2021-01-27 | GSE139136 | GEO
Project description:Single-cell ATAC-Seq of recurrent pediatric high-grade glioma
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Project description:Pediatric high-grade gliomas (pHGGs), including glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG), are highly morbid childhood brain tumors. Even with treatment, overall survival is poor, making pHGG the number one cause of cancer death in children. Up to 80% of DIPGs harbor a somatic missense mutation in genes encoding Histone H3 proteins. To investigate whether this H3K27M mutation is associated with distinct chromatin structure that alters transcription regulation, we generated the first high-resolution Hi-C maps of pHGG cell lines and tumor tissue. By integrating transcriptome (RNA-Seq), enhancer landscape (ChIP-Seq), genome structure (Hi-C), and chromatin accessibility (ATAC-Seq) datasets from H3K27M mutant and wild-type specimens, we identified tumor specific enhancers and regulatory networks for known oncogenes. In addition, we identified distinct genomic structural variations that lead to enhancer hijacking and gene co-amplification, including A2M, JAG2, FLRT1.
2021-06-03 | GSE162976 | GEO
Project description:Purpose of reviewPediatric low-grade gliomas (pLGGs) have been treated with similar therapies for the last 30 years. Recent biological insights have allowed a new generation of targeted therapies to be developed for these diverse tumors. At the same time, technological advances may redefine the late toxicities associated with radiation therapy. Understanding recent developments in pLGG therapy is essential to the management of these common pediatric tumors.Recent findingsIt is now well understood that aberrations of the mitogen-activated protein kinase pathway are key to oncogenesis in low-grade gliomas. This understanding, along with the development of available targeted agents, have heralded a new era of understanding and treatment for these patients. Promising, sustained responses are now being seen in early phase trials among patients with multiply recurrent/progressive disease. Also, newer and highly conformal radiation approaches such as proton beam radiotherapy maintain efficacy of radiation but limit radiation-associated toxicities.SummaryNovel therapies offer the potential for tumor control with greatly reduced toxicities. However, late effects of these therapies are just now being explored. Improved radiation approaches and targeted agents have the potential to redefine traditional therapy for pLGG.
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Project description:Low-grade glioma (LGG) is the most common brain tumor in children and has excellent long-term survival. With an excellent survival rate, the choice of treatment involves careful consideration of minimizing late toxicity from surgery, radiation, and chemotherapy. Surgery, radiation therapy, and chemotherapy can be used as monotherapy or in combination, providing different therapeutic ratios and complications. As a result, establishing the selection of ideal therapies has been a controversial area, presenting challenges. Recent advances in understanding molecular characteristics of pediatric LGG affect classification and treatment approaches. This review aims to overview recent developments in medical treatment in pediatric LGG.
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Project description:BackgroundTo evaluate efficacy, pharmacokinetics (PK) and pharmacodynamics of single-agent everolimus in pediatric patients with radiographically progressive low-grade glioma (LGG).MethodsEverolimus was administered at 5 mg/m2 once daily as a tablet or liquid for a planned 48-week duration or until unacceptable toxicity or disease progression. Patients with neurofibromatosis type 1 were excluded. PK and pharmacodynamic endpoints were assessed in consenting patients.ResultsTwenty-three eligible patients (median age 9.2 years) were enrolled. All patients received prior chemotherapy (median number of prior regimens two) and/or radiotherapy (two patients). By week 48, two patients had a partial response, 10 stable disease, and 11 clinical or radiographic progression; two discontinued study prior to 1 year (toxicity: 1, physician determination: 1). With a median follow up of 1.8 years (range 0.2-6.7 years), the 2-, 3-, and 5-year progression-free survivals (PFS) were 39 ± 11%, 26 ± 11%, and 26 ± 11%, respectively; two patients died of disease. The 2-, 3-, and 5-year overall survival (OS) were all 93 ± 6%. Grade 1 and 2 toxicities predominated; two definitively related grade 3 toxicities (mucositis and neutropenia) occurred. Grade 4 elevation of liver enzymes was possibly related in one patient. Predose blood levels showed substantial variability between patients with 45.5% below and 18.2% above the target range of 5-15 ng/mL. Pharmacodynamic analysis demonstrated significant inhibition in phospho-S6, 4E-BP1, and modulation of c-Myc expression.ConclusionDaily oral everolimus provides a well-tolerated, alternative treatment for multiple recurrent, radiographically progressive pediatric LGG. Based on these results, everolimus is being investigated further for this patient population.
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Project description:Background: Glioblastoma mortality is driven by tumour progression or recurrence despite administering a therapeutic arsenal consisting of surgical resection, radiation, and alkylating chemotherapy. The genetic changes underlying tumour progression and chemotherapy resistance are poorly understood. Methods: In this work, we sought to define the relationship between EGFR amplification status, EGFR mRNA expression, and EGFR pathway activity. We compared RNA-sequencing data from matched primary and recurrent tumour samples (N = 40 patients, 20 with EGFR amplification). Results: In the setting of glioblastoma recurrence, the EGFR pathway was overexpressed regardless of EGFR amplification status, suggesting a common genomic endpoint in recurrent glioblastoma, although EGFR amplification did associate with higher EGFR mRNA expression. Three of forty patients in the study cohort had EGFR-amplified tumours and received targeted EGFR therapy. Their molecular subtypes and clinical outcomes did not significantly differ from patients who received conventional chemotherapy. Conclusion: Our findings suggest that while the EGFR amplification may confer a unique molecular profile in primary glioblastoma, pathway analysis reveals upregulation of the EGFR pathway in recurrence, regardless of amplification status. As such, the EGFR pathway may be a key mediator of glioblastoma progression.
2023-01-25 | GSE222515 | GEO
Project description:Recurrent pediatric high-grade glioma is a leading cause of cancer-related death in children. We report results of a systematic review and meta-analysis investigating survival outcome in pediatric patients with recurrent high-grade glioma over the last 20 years. MEDLINE/PubMed, EMBASE, Web of Science and Cochrane Review databases were searched for relevant studies reporting on survival outcomes for pediatric patients with recurrent high-grade glioma treated between 1996 and 2016. Progression-free survival (PFS) and overall survival (OS) were calculated cumulatively over all studies, by therapy subgroup, and by decade of treatment. Random effects models were used to control for heterogeneity as measured by the I2 statistic. A total of 17 studies across 4 treatment strategies were included. Eleven investigated traditional chemotherapy, 1 investigated targeted therapy, 3 investigated immunotherapy, and 2 investigated radiotherapy. A total of 129 patients were included with a median age of 10.0 years. Cumulative PFS was 3.5 months (95% CI 2.1-5.0). Cumulative OS was 5.6 months (95% CI 3.9-7.3). OS was 4.0 months (95% CI 1.9-6.1) using traditional chemotherapy, 9.3 months using targeted therapies (95% CI 5.4-13), 6.9 months using immunotherapy (95% CI 2.1-12), and 14 months using reirradiation (95% CI 2.8-25). OS between 1996 and 2006 was 4.2 months (95% CI 2.1-6.2) compared to 8.5 months (95% CI 5.6-11) after 2006. Pediatric patients with recurrent high-grade glioma suffer from poor PFS and OS, regardless of therapy. There may be a trend towards improved OS in the last decade.
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Project description:This study aimed to assess the incidence and management of pseudoprogression after radiation therapy (RT) in patients with pediatric low-grade glioma (LGG). This retrospective review included patients aged 21 years or younger with intracranial LGG treated with curative-intent RT. Pseudoprogression was defined as an increase in tumor size by ≥10% in at least two dimensions between two and three consecutive MR imaging studies. Overall survival (OS) and event-free survival (EFS) were measured from the first day of RT. EFS was defined as survival without true progression or secondary high-grade glioma. Sixty-two of 221 patients developed pseudoprogression, with a 10-year cumulative incidence of 29.0% (95% CI 23.0-35.2). Median time to pseudoprogression was 6.1 months after RT. Symptomatic pseudoprogression was managed with subtotal resection, shunt/Ommaya reservoir placement, or corticosteroids in 11 (18%), 7 (11%), and 2 patients (3%), respectively. The remaining tumors were observed (68%). Patients with pilocytic astrocytoma (PA) had 5.4-fold greater odds of developing pseudoprogression relative to tumors of other histology (odds ratio 95% CI 2.5-11.4, P < 0.0001). Among patients with PA (n = 127), the 10-year cumulative incidence of pseudoprogression was 42.9%. In this group, pseudoprogression was associated with improved 10-year EFS (84.5% vs. 58.5%, P = 0.008) and OS (98.0% vs. 91.2%, P = 0.03). Pseudoprogression after irradiation was common, especially in patients with pilocytic astrocytoma, and was associated with improved survival. Knowledge of the incidence and temporal course of pseudoprogression may help avoid unnecessary salvage therapy.
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