Epigenetic mechanisms regulating neural development and pediatric brain tumor formation

2011 ◽  
Vol 8 (2) ◽  
pp. 119-132 ◽  
Author(s):  
Claudia M. C. Faria ◽  
James T. Rutka ◽  
Christian Smith ◽  
Paul Kongkham
Keyword(s):  
Brain Tumors ◽  
Neural Development ◽  
Treatment Strategies ◽  
Pediatric Brain Tumor ◽  
Pediatric Brain Tumors ◽  
Tumor Formation ◽  
Cancer Epigenetics ◽  
Development And Differentiation ◽  
Altered Gene ◽  
Pediatric Brain

Pediatric brain tumors are the leading cause of cancer-related death in children, and among them, embryonal tumors represent the largest group with an associated poor prognosis and long-term morbidity for survivors. The field of cancer epigenetics has emerged recently as an important area of investigation and causation of a variety of neoplasms, and is defined as alterations in gene expression without changes in DNA sequence. The best studied epigenetic modifications are DNA methylation, histone modifications, and RNA-based mechanisms. These modifications play an important role in normal development and differentiation but their dysregulation can lead to altered gene function and cancer. In this review the authors describe the mechanisms of normal epigenetic regulation, how they interplay in neuroembryogenesis, and how these can cause brain tumors in children when dysregulated. The potential use of epigenetic markers to design more effective treatment strategies for children with malignant brain tumors is also discussed.

scholarly journals A pediatric brain tumor atlas of genes deregulated by somatic genomic rearrangement

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yiqun Zhang ◽  
Fengju Chen ◽  
Lawrence A. Donehower ◽  
Michael E. Scheurer ◽  
Chad J. Creighton
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Tyrosine Kinases ◽  
Pediatric Brain Tumor ◽  
Pediatric Brain Tumors ◽  
Altered Expression ◽  
Critical Pathways ◽  
Cis Regulation ◽  
Or Gene ◽  
Pediatric Brain

AbstractThe global impact of somatic structural variants (SSVs) on gene expression in pediatric brain tumors has not been thoroughly characterised. Here, using whole-genome and RNA sequencing from 854 tumors of more than 30 different types from the Children’s Brain Tumor Tissue Consortium, we report the altered expression of hundreds of genes in association with the presence of nearby SSV breakpoints. SSV-mediated expression changes involve gene fusions, altered cis-regulation, or gene disruption. SSVs considerably extend the numbers of patients with tumors somatically altered for critical pathways, including receptor tyrosine kinases (KRAS, MET, EGFR, NF1), Rb pathway (CDK4), TERT, MYC family (MYC, MYCN, MYB), and HIPPO (NF2). Compared to initial tumors, progressive or recurrent tumors involve a distinct set of SSV-gene associations. High overall SSV burden associates with TP53 mutations, histone H3.3 gene H3F3C mutations, and the transcription of DNA damage response genes. Compared to adult cancers, pediatric brain tumors would involve a different set of genes with SSV-altered cis-regulation. Our comprehensive and pan-histology genomic analyses reveal SSVs to play a major role in shaping the transcriptome of pediatric brain tumors.

scholarly journals DIPG-60. PILOT STUDY OF CIRCULATING TUMOR CELLS IN PEDIATRIC HIGH GRADE BRAIN TUMORS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii299-iii299
Author(s):  
Wafik Zaky ◽  
Long Dao ◽  
Dristhi Ragoonanan ◽  
Izhar Bath ◽  
Sofia Yi ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Pediatric Brain Tumor ◽  
Pediatric Brain Tumors ◽  
Disease Assessment ◽  
Liquid Biopsies ◽  
Capture Method ◽  
Pediatric Brain

Abstract BACKGROUND Despite its increasing use, circulating tumor cells (CTCs) have not been studied in pediatric brain tumors. METHODS Cell surface vimentin (CSV) is a marker for CTC detection. We developed an automated CSV-based CTC capture method for pediatric brain tumor using the Abnova Cytoquest platform. PBMCs isolated from blood samples from 52 brain tumor patients were processed to isolate CSV+ CTCs. Captured cells were then stained for CSV and CD45 and scanned to determine the number of CTCs. DIPG samples were additionally examined for H3K27M expression on CSV+ cells. Long term cancer survivors were used as a control cohort. RESULTS 86.4% of all the samples exhibited between 1–13 CSV+ CTCs, with a median of 2 CSV+ CTCs per sample. Using a value of ≥ 1 CTC as a positive result, the sensitivity and specificity of this test was 83.05% and 60.0% respectively. 19 DIPG samples were analyzed and 70% (13 samples) were positive for 1–5 CTCs. Five of these 7 positive CSV+ CTCs DIPG samples were also positive for H3K27M mutations by immunohistochemistry (71%). Mean survival in days for the CTC positive and negative DIPG samples were 114 and 211 days, respectively (p= 0.13). CONCLUSION This is the first study of CTCs in pediatric CNS tumors using an automated approach. Patients with brain tumors can exhibit CSV+ CTCs within peripheral blood. The use of specific molecular markers such as H3K27M can improve the diagnostic capability of liquid biopsies and may enable future disease assessment for personalized therapy.

scholarly journals SL1 GENETICS OF PEDIATRIC BRAIN TUMORS: RECENT ADVANCES AND FUTURE PERSPECTIVES

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii1-ii1
Author(s):  
David T W Jones
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Somatic Hypermutation ◽  
Tumor Biology ◽  
Pediatric Brain Tumor ◽  
Pediatric Brain Tumors ◽  
Braf V600e ◽  
Enhancer Element ◽  
Frequent Mutations ◽  
Pediatric Brain

Abstract The last decade has seen a true revolution in our understanding of the oncogenic mechanisms underlying human tumors, brought about by transformative advances in the technologies available to interrogate the (epi)genetic composition of cancer cells. The dynamic pediatric neuro-oncology community has proven to be very agile in adapting to these changes, and has arguably been at the forefront of some of the most exciting new discoveries in tumor biology in recent years. For example, high-throughput genomic sequencing has revealed highly frequent mutations in histone genes in pediatric glioblastoma; highlighted an ever-expanding role for oncogenic gene fusions in multiple pediatric brain tumor types, and also shed light on novel phenotypic patterns such as chromothripsis (dramatic chromosomal shattering) and somatic hypermutation - the latter being a possible marker for response to novel immunotherapeutic approaches. Epigenetic profiling has also identified a role for ‘enhancer hijacking’ (whereby genomic rearrangement brings an active enhancer element in close proximity to a proto-oncogene) in multiple pediatric brain tumors, and is even pointing towards a fundamentally new way in which tumors may be molecularly classified. In coming years, the major challenge will be to harness the power of these discoveries to more accurately diagnose patients and to identify potential therapeutic targets in a more personalized way, so that these major biological advances can also be translated into substantial clinical benefit. Examples such as the dramatic responses observed in childhood brain tumor sufferers to BRAF V600E and NTRK inhibitors demonstrate the promise that such an approach can hold, but it will require a fundamental shift in the way that clinical trials are planned and conducted in order to optimize patient care. This talk will highlight some of the most striking developments in the field, and look at the challenges that remain before these can lead to improved patient outcomes.

scholarly journals Exploratory Evaluation of MR Permeability with 18F-FDG PET Mapping in Pediatric Brain Tumors: A Report from the Pediatric Brain Tumor Consortium

2013 ◽  
Vol 54 (8) ◽  
pp. 1237-1243 ◽  
Author(s):  
K. A. Zukotynski ◽  
F. H. Fahey ◽  
S. Vajapeyam ◽  
S. S. Ng ◽  
M. Kocak ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Fdg Pet ◽  
Pediatric Brain Tumor ◽  
Pediatric Brain Tumors ◽  
18F Fdg ◽  
Pediatric Brain

scholarly journals Circular RNA expression profiles in pediatric ependymomas

2020 ◽  
Author(s):  
Ulvi Ahmadov ◽  
Meile M. Bendikas ◽  
Karoline K. Ebbesen ◽  
Astrid M. Sehested ◽  
Jorgen Kjems ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Pilocytic Astrocytoma ◽  
Expression Profiles ◽  
Pediatric Brain Tumor ◽  
Pediatric Brain Tumors ◽  
Disease Stage ◽  
Tumor Subtypes ◽  
Pediatric Brain ◽  
Control Samples

Pediatric brain tumors frequently develop in the cerebellum, where ependymoma, medulloblastoma and pilocytic astrocytoma are the most prevalent subtypes. These tumors are currently treated using non-specific therapies, in part because few somatically mutated driver genes are present, and the underlying pathobiology is poorly described. Circular RNAs (circRNAs) have recently emerged as a large class of primarily non-coding RNAs with important roles in tumorigenesis, but so far they have not been described in pediatric brain tumors. To advance our understanding of these tumors, we performed high-throughput sequencing of ribosomal RNA-depleted total RNA from 10 primary ependymoma and 3 control samples. CircRNA expression patterns were determined using two independent bioinformatics algorithms, and correlated to disease stage, outcome, age, and gender. We found a profound global downregulation of circRNAs in ependymoma relative to control samples. Many differentially expressed circRNAs were discovered and circSMARCA5 and circ-FBXW7, which are described as tumor suppressors in glioma and glioblastomas in adults, were among the most downregulated. Moreover, patients with a dismal outcome clustered separately from patients with a good prognosis in unsupervised hierarchical cluster analyses. Next, we performed NanoString nCounter experiments using a custom-designed panel including 66 selected circRNA targets and analyzed formalin-fixed paraffin-embedded (FFPE) samples from a larger cohort of ependymoma patients as well as patients diagnosed with medulloblastoma or pilocytic astrocytoma. These experiments were used to validate our findings and, in addition, indicated that circRNA expression profiles are different among distinct pediatric brain tumor subtypes. In particular, circRMST and a circRNA derived from the LRBA gene were specifically upregulated in ependymomas. In conclusion, circRNAs have profoundly different expression profiles in ependymomas relative to controls and other pediatric brain tumor subtypes.

scholarly journals SURG-24. NOVEL MALLEABLE FORCIPES FOR ENDOSCOPIC ASSISTED TECHNIQUE IN PEDIATRIC BRAIN TUMORS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii464-iii464
Author(s):  
Yukiko Nakahara ◽  
Hiroshi Ito ◽  
Fumitaka Yoshioka ◽  
Kohei Inoue ◽  
Atsushi Ogata ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Tumor Resection ◽  
Pediatric Brain Tumor ◽  
Pediatric Brain Tumors ◽  
Optical Devices ◽  
Surgical Instruments ◽  
Vascular Structure ◽  
Maximum Angle ◽  
Surgical Field ◽  
Pediatric Brain

Abstract Recent advances in optical devices and surgical instruments have been applied to neurosurgery. Even with modifications, one of the most serious risks is injury of neuronal and vascular structure caused by operation of surgical instruments in a narrow surgical field. Fixed instruments are not practical for pediatric brain tumor surgeries because the length of the curved or angled tip portion is limited because of the narrow entrance. We developed a novel malleable forceps to resolve the difficulties related to microsurgical procedures. The malleable forceps has two shafts with a sharp cup at the tip. The entire forceps was made of stainless steel, with a silver and nickel alloy inserted between 10 and 40 mm from the tip. In the alloy part, the surgeon can flex the forceps freely using a special cylinder. The special cylinder is useful to prevent from slipping of the cups of tip. The maximum angle that can be bent is 70 degrees vertically. We also developed a monoshaft malleable forceps. We used these flexible forcipes in the case of various pediatric brain tumors including craniopharyngioma. We performed tumor resection by anterior interhemispheric trans-lamina terminalis approach. After procedure of tumor resection using microscope, endoscope inserted around the pituitary stalk. The piece of calcified tumor could be easily removed without any complications. These forcipes can be deformed to an appropriate angle and can be applied to various cases, especially pediatric brain tumors.

scholarly journals Pediatric Brain Tumors: Innovative Genomic Information Is Transforming the Diagnostic and Clinical Landscape

2015 ◽  
Vol 33 (27) ◽  
pp. 2986-2998 ◽  
Author(s):  
Amar Gajjar ◽  
Daniel C. Bowers ◽  
Matthias A. Karajannis ◽  
Sarah Leary ◽  
Hendrik Witt ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Treatment Strategies ◽  
Genomic Analysis ◽  
Pediatric Brain Tumors ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Collaborative Group ◽  
Treatment Protocols ◽  
New Information ◽  
Atypical Teratoid ◽  
Pediatric Brain

Pediatric neuro-oncology has undergone an exciting and dramatic transformation during the past 5 years. This article summarizes data from collaborative group and institutional trials that have advanced the science of pediatric brain tumors and survival of patients with these tumors. Advanced genomic analysis of the entire spectrum of pediatric brain tumors has heralded an era in which stakeholders in the pediatric neuro-oncology community are being challenged to reconsider their current research and diagnostic and treatment strategies. The incorporation of this new information into the next-generation treatment protocols will unleash new challenges. This review succinctly summarizes the key advances in our understanding of the common pediatric brain tumors (ie, medulloblastoma, low- and high-grade gliomas, diffuse intrinsic pontine glioma, and ependymoma) and some selected rare tumors (ie, atypical teratoid/rhabdoid tumor and CNS primitive neuroectodermal tumor). The potential impact of this new information on future clinical protocols also is discussed. Cutting-edge genomics technologies and the information gained from such studies are facilitating the identification of molecularly defined subgroups within patients with particular pediatric brain tumors. The number of evaluable patients in each subgroup is small, particularly in the subgroups of rare diseases. Therefore, international collaboration will be crucial to draw meaningful conclusions about novel approaches to treating pediatric brain tumors.

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