Central Role of C2H2-Type Zinc Finger-Containing Genes in Pediatric Brain Tumors

Zinc fingers consist of one of the most abundant motifs in transcription factors and DNA-binding proteins. Recent studies provide evidence on the pathological implication of zinc finger proteins in various neurodevelopmental disorders and malignancies but their role in pediatric brain tumors is largely unexplored. To this end, we investigated the differential expression of zinc finger-containing genes along with relevant biological processes and pathways among four main brain tumor categories (pilocytic astrocytomas, ependymomas, medulloblastomas and glioblastomas). By employing an extended bioinformatic toolset, we performed a preliminary in silico study in order to identify the expression of zinc finger-containing genes and associated functions in pediatric brain tumors. Our data analysis reveals the prominent role of C2H2-type zinc finger-containing genes in the molecular mechanisms underlying pediatric brain tumors followed by the Ring and PHD finger types. Significant dysregulation of ABLIM2 and UHFR1 genes was detected in all tumor types drawing attention to the dysregulation of cell polarization process and Ubiquitin-Proteasome System (UPS) in the pathogenesis of pediatric brain tumors. Moreover, significant gene clustering was observed in multiple locations with two highly visible clusters revealing a contrast in gene regulation between medulloblastomas and the other three brain tumor types, indicating a promising area of future research.

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

Nature Communications ◽

10.1038/s41467-021-21081-y ◽

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.

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

Neuro-Oncology ◽

10.1093/neuonc/noaa222.105 ◽

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.

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Exploiting Laboratory Insights to Improve Outcomes of Pediatric Central Nervous System Tumors

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_159149 ◽

2016 ◽

pp. e540-e546 ◽

Cited By ~ 2

Author(s):

Giles W. Robinson ◽

Hendrik Witt ◽

Adam Resnick

Keyword(s):

Brain Tumor ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Pediatric Brain Tumor ◽

Pediatric Brain Tumors ◽

Low Grade ◽

Short Period ◽

Tumor Management ◽

The Impact ◽

Pediatric Brain

Over a relatively short period of time, owing to improvements in biotechnology, our ability to identify the molecular mechanisms within pediatric brain tumors has dramatically increased. These findings have reshaped the way that we describe these diseases and have provided insights into how to better treat these often devastating diseases. Although still far from reaching the full therapeutic potential these advancements hold, the impact of these findings is steadily taking hold of pediatric brain tumor management. In this article, we summarize the major discoveries within three common pediatric brain tumor categories; medulloblastoma, ependymoma, and low-grade glioma. We discuss the current impact of these findings on treatment and the direction these findings may take the field of pediatric neuro-oncology.

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Pediatric Brain Tumors: Imaging of Late Effects in Pediatric Brain Tumor Survivors

Imaging of Complications and Toxicity following Tumor Therapy - Medical Radiology ◽

10.1007/174_2015_1084 ◽

2015 ◽

pp. 171-192

Author(s):

G. Tallen ◽

M. Warmuth-Metz ◽

P. Hernáiz Driever ◽

Stefan M. Pfister

Keyword(s):

Brain Tumor ◽

Brain Tumors ◽

Late Effects ◽

Pediatric Brain Tumor ◽

Pediatric Brain Tumors ◽

Pediatric Brain

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18F-FDG PET and MR Imaging Associations Across a Spectrum of Pediatric Brain Tumors: A Report from the Pediatric Brain Tumor Consortium

Journal of Nuclear Medicine ◽

10.2967/jnumed.114.139626 ◽

2014 ◽

Vol 55 (9) ◽

pp. 1473-1480 ◽

Cited By ~ 21

Author(s):

K. Zukotynski ◽

F. Fahey ◽

M. Kocak ◽

L. Kun ◽

J. Boyett ◽

...

Keyword(s):

Brain Tumor ◽

Brain Tumors ◽

Mr Imaging ◽

Fdg Pet ◽

Pediatric Brain Tumor ◽

Pediatric Brain Tumors ◽

18F Fdg ◽

Pediatric Brain

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EXTH-73. HETEROGENEITY IN CELL SURFACE ANTIGEN AND HLA CLASS I EXPRESSION IN PEDIATRIC BRAIN TUMORS AND ITS IMPACT ON T-CELL IMMUNOTHERAPY

Neuro-Oncology ◽

10.1093/neuonc/noaa215.427 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii103-ii103

Author(s):

Haley Houke ◽

Xiaoyan Zhu ◽

Kimberly S Mercer ◽

Jennifer L Stripay ◽

Jason Chiang ◽

...

Keyword(s):

T Cells ◽

Brain Tumor ◽

T Cell ◽

Brain Tumors ◽

Cell Surface ◽

Hla Class I ◽

Pediatric Brain Tumors ◽

Class I ◽

Car T ◽

Pediatric Brain

Abstract Immunotherapy with tumor antigen-specific chimeric antigen receptor (CAR) and/or ab (T-cell receptor) TCR T-cells has the potential to improve clinical outcomes of patients with pediatric brain tumors. As a prerequisite for successful T-cell therapies, we must determine which cell surface antigens are expressed and targetable in these tumors, and if HLA Class I is present, which is necessary for ab TCR T-cell recognition. Therefore, in this study we systematically analyzed pediatric patient-derived orthotopic xenograft (PDOX) brain tumor samples for cell surface expression of five known CAR targets: IL13Ra2, HER2, EphA2, B7-H3, and GD2, as well as HLA Class I. We established and validated a flow cytometry-based method of profiling tumor-associated antigens. Fifty-three PDOX samples have been profiled to date, including medulloblastoma, high grade glioma (HGG), diffuse intrinsic pontine glioma (DIPG), atypical teratoid rhabdoid tumor (ATRT), and ependymoma, among others. Our results showed high variability within and between individual samples. B7-H3 was the most consistently expressed, seen in 98% of the samples tested. We validated these results by conventional immunohistochemistry staining for B7-H3 and found comparable RESULTS: HLA Class I was highly expressed on all HGG samples but was undetectable on 47.8% of other brain tumor samples. This suggests that down-regulation of HLA class I is one mechanism by which brain tumors evade conventional T-cells, and that HLA-independent CAR T-cells would be useful therapies. We also compared expression of antigens in fresh patient samples and corresponding PDOX tumors and saw that they were indeed similar. To our knowledge, this is the largest group of pediatric brain tumor PDOX samples methodically analyzed for potential CAR target antigens and HLA Class I. Taken together, our data demonstrate that elimination of tumors by CAR T-cell immunotherapies will require targeting multiple antigens, and our profiling method could inform how to circumvent antigen-negative relapse.

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

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz039.001 ◽

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.

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