scholarly journals Liquid Biomarkers for Pediatric Brain Tumors: Biological Features, Advantages and Perspectives

2020 ◽  
Vol 10 (4) ◽  
pp. 254
Author(s):  
Sibylle Madlener ◽  
Johannes Gojo
Keyword(s):  
Brain Tumors ◽  
Liquid Biopsy ◽  
Current Knowledge ◽  
Clinical Care ◽  
Tumor Biology ◽  
Pediatric Brain Tumors ◽  
Genetic Alterations ◽  
Tumor Type ◽  
Molecular Alterations ◽  
Pediatric Brain

Tumors of the central nervous system are the most frequent solid tumor type and the major cause for cancer-related mortality in children and adolescents. These tumors are biologically highly heterogeneous and comprise various different entities. Molecular diagnostics are already well-established for pediatric brain tumors and have facilitated a more accurate patient stratification. The availability of targeted, biomarker-driven therapies has increased the necessity of longitudinal monitoring of molecular alterations within tumors for precision medicine-guided therapy. Nevertheless, diagnosis is still primarily based on analyses of the primary tumor and follow-up is usually performed by imaging techniques which lack important information on tumor biology possibly changing the course of the disease. To overcome this shortage of longitudinal information, liquid biopsy has emerged as a promising diagnostic tool representing a less-invasive source of biomarkers for tumor monitoring and therapeutic decision making. Novel ultrasensitive methods for detection of allele variants, genetic alterations with low abundance, have been developed and are promising tools for establishing and integrating liquid biopsy techniques into clinical routine. Pediatric brain tumors harbor multiple molecular alterations with the potential to be used as liquid biomarkers. Consequently, studies have already investigated different types of biomarker in diverse entities of pediatric brain tumors. However, there are still certain pitfalls until liquid biomarkers can be unleashed and implemented into routine clinical care. Within this review, we summarize current knowledge on liquid biopsy markers and technologies in pediatric brain tumors, their advantages and drawbacks, as well as future potential biomarkers and perspectives with respect to clinical implementation in patient care.

scholarly journals TBIO-18. LIQUID BIOPSY DETECTION OF GENOMIC ALTERATIONS IN PEDIATRIC BRAIN TUMORS FROM CELL FREE DNA IN PERIPHERAL BLOOD, CSF, AND URINE

2018 ◽  
Vol 20 (suppl_2) ◽  
pp. i184-i184
Author(s):  
Melanie Pages ◽  
Denisse Rotem ◽  
Gregory Gydush ◽  
Sarah Reed ◽  
Justin Rhoades ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Peripheral Blood ◽  
Liquid Biopsy ◽  
Pediatric Brain Tumors ◽  
Genomic Alterations ◽  
Cell Free Dna ◽  
Free Dna ◽  
Pediatric Brain

scholarly journals GENE-07. LIQUID BIOPSY DETECTION OF GENOMIC ALTERATIONS IN PEDIATRIC BRAIN TUMORS FROM CELL-FREE DNA IN PERIPHERAL BLOOD, CSF, AND URINE

2019 ◽  
Vol 21 (Supplement_2) ◽  
pp. ii82-ii82
Author(s):  
Mélanie Pagès ◽  
Denisse Rotem ◽  
Gregory Gydush ◽  
Sarah Reed ◽  
Justin Rhoades ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Peripheral Blood ◽  
Liquid Biopsy ◽  
Pediatric Brain Tumors ◽  
Genomic Alterations ◽  
Cell Free Dna ◽  
Free Dna ◽  
Pediatric Brain

scholarly journals INNV-22. LIQUID BIOPSY DETECTION OF GENOMIC ALTERATIONS IN PEDIATRIC BRAIN TUMORS FROM CELL FREE DNA IN PERIPHERAL BLOOD, CSF, AND URINE

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi142-vi143
Author(s):  
Mélanie Pages ◽  
Denisse Rotem ◽  
Gregory Gydush ◽  
Sarah Reed ◽  
Justin Rhoades ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Peripheral Blood ◽  
Liquid Biopsy ◽  
Pediatric Brain Tumors ◽  
Genomic Alterations ◽  
Cell Free Dna ◽  
Free Dna ◽  
Pediatric Brain

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 Global molecular alterations involving recurrence or progression of pediatric brain tumors

Neoplasia ◽  
2022 ◽  
Vol 24 (1) ◽  
pp. 22-33
Author(s):  
Fengju Chen ◽  
Darshan S. Chandrashekar ◽  
Michael E. Scheurer ◽  
Sooryanarayana Varambally ◽  
Chad J. Creighton
Keyword(s):  
Brain Tumors ◽  
Pediatric Brain Tumors ◽  
Molecular Alterations ◽  
Pediatric Brain

scholarly journals PATH-56. PYROSEQUENCING METHOD FOR RAPID DETECTION OF KIAA1549-BRAF FUSION GENES IN PEDIATRIC BRAIN TUMORS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi156-vi156
Author(s):  
Yuzaburo Shimizu ◽  
Satoshi Adachi ◽  
Mario Suzuki ◽  
Osamu Akiyama ◽  
Ikuko Ogino ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Rna Extraction ◽  
Rna Isolation ◽  
Pediatric Brain Tumors ◽  
Diagnostic Value ◽  
Genetic Alterations ◽  
Diffuse Astrocytoma ◽  
Fusion Genes ◽  
Braf Fusion ◽  
Pediatric Brain

Abstract BACKGROUND Fusion genes driving tumorigenesis have drawn the attention of oncologists and researchers. Recently, independent genomic researchers have identified a tandem duplication of BRAF at 7q34 that leads to several KIAA1549-BRAF gene exon fusions in the majority of pilocytic astrocytoma (PA). Because KIAA1549-BRAF fusion transcripts are usually absent in diffuse astrocytoma, these genetic alterations may have diagnostic value. Despite the importance of such molecular alterations, there are no comprehensive reproducible methods to detect these fusion genes. METHODS Samples of brain tumors were selected retrospectively from our institution. 22 pediatric brain tumors of five types, namely PA, oligodendroglioma (OD), anaplastic astrocytoma (AA), glioblastoma (GBM) and, ganglioglioma (GG), were evaluated to detect KIAA1549-BRAF fusion genes using a pyrosequencing-based method following RNA isolation, cDNA synthesis and real-time polymerase chain reaction. We designed the primers to detect the three most common fusion variants: KIAA1549 ex15-BRAF ex9, KIAA1549 ex16-BRAF ex9, and KIAA1549 ex16-BRAF ex11. RESULTS Our method successfully detected KIAA1549-BRAF fusion in 16 out of 22 samples, that is, eleven PA, two OD, one AA, one GBM, and one GG. The entire procedure from RNA extraction to obtaining mutation data was performed within 2 hours. CONCLUSION A comprehensive method for detecting fusion genes in pediatric brain tumors was evaluated. This method identified KIAA1549–BRAF fusion variants quickly compared to other methods. Our results will be useful for studies on intraoperative diagnosis and classification of tumors for improving surgical decisions.

scholarly journals SEIZURES IN CHILDREN WITH LOW GRADE GLIOMA

2021 ◽  
Vol 7 (1) ◽  
pp. 60-65
Author(s):  
Piyush Ostwal ◽  
Shanbhag Nandan
Keyword(s):  
Brain Tumors ◽  
Pediatric Brain Tumors ◽  
Dysembryoplastic Neuroepithelial Tumor ◽  
Histopathological Diagnosis ◽  
Low Grade ◽  
Tumor Type ◽  
Low Grade Gliomas ◽  
Primary Treatment Modality ◽  
Antiepileptic Medications ◽  
Pediatric Brain

Seizures are a common presentation of pediatric brain tumors. The incidence of pediatric brain tumor (Age 0-19 years) ranges from 1.12–5.26 cases per 100,000 persons. Low grade gliomas are an important subgroup of pediatric brain tumors causing epilepsy. Low-grade gliomas are largely slow-growing tumors and the manifestations are dependent on age, location, tumor type, size of tumor and rate of tumor growth. Seizures have been reported in up to 38 % of children with supratentorial tumors. The tumors are identified when work up of patients for epilepsy includes electrophysiological and imaging studies. The primary treatment modality remains surgical excision. Antiepileptic medications are used for control of seizures. Subsequent histopathological diagnosis is important for prognostication. The tumors commonly associated with long-term epilepsy in various studies were ganglioglioma, dysembryoplastic neuroepithelial tumor, pilocytic astrocytoma and pilocytic xanthoastrocytoma. The outcome of surgery with regards to seizure control is generally good. Though concomitantly antiepileptic medications will be needed for most of them. An attempt is made in this review to summarize the epidemiology, clinical features, pathology and treatment aspects of pediatric low grade gliomas presenting with seizures.

Year 1 in the Molecular Era of Pediatric Brain Tumor Diagnosis: Application of Universal Clinical Targeted Sequencing in an Unselected Cohort of Children

2018 ◽  
pp. 1-13
Author(s):  
Bonnie L. Cole ◽  
Christina M. Lockwood ◽  
Shannon Stasi ◽  
Jeffrey Stevens ◽  
Amy Lee ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Clinical Laboratory ◽  
Pediatric Brain Tumors ◽  
Genetic Alterations ◽  
Targeted Sequencing ◽  
Low Grade ◽  
Clinical Tool ◽  
Pilot Studies ◽  
Pediatric Brain

Purpose Next-generation sequencing is gaining acceptance as a clinical tool to aid diagnosis and guide treatment of pediatric cancer. Prior pilot studies have evaluated the feasibility and utility of clinical genomic profiling in a subset of selected patients with brain tumors. Here, we report an unselected prospective cohort study to evaluate the clinical use of universal targeted sequencing in pediatric patients with brain tumors. Methods We applied a universal sequencing protocol for all tumors of the CNS undergoing diagnostic workup at Seattle Children’s Hospital during the study period of November 2015 to November 2016. All tumors were sequenced using the UW-OncoPlex platform, which is a multiplexed targeted deep gene sequencing panel that detects genetic alterations in 262 cancer-related genes performed in a College of American Pathologists–accredited Clinical Laboratory Improvements Amendments–certified laboratory. Results Eighty-eight patients underwent diagnostic evaluation during the study period, of which 85 tumors (95%) yielded sufficient DNA for sequencing, including 59 newly diagnosed and 26 relapsed. Clinically relevant genetic alterations were identified in 68 of 85 patients (80%). Of these, 57 (67%) had disease-defining or disease-modifying mutations, 44 (52%) had potentially targetable mutations, and 31 (36%) had mutations requiring germline follow-up. As of the last follow-up, seven patients had been prescribed targeted agents on the basis of sequencing results, and nine had confirmed deleterious germline mutations. Conclusion Clinically validated molecular profiling of pediatric brain tumors aids diagnosis and treatment of patients with a variety of high- and low-grade primary and relapsed pediatric brain tumors.

scholarly journals Clinical Utility of GlioSeq Next-Generation Sequencing Test in Pediatric and Young Adult Patients With Brain Tumors

2019 ◽  
Vol 78 (8) ◽  
pp. 694-702
Author(s):  
Somak Roy ◽  
Sameer Agnihotri ◽  
Soufiane El Hallani ◽  
Wayne L Ernst ◽  
Abigail I Wald ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Young Adult ◽  
Brain Tumors ◽  
Clinical Utility ◽  
Pediatric Brain Tumors ◽  
Genetic Alterations ◽  
Adult Patients ◽  
Next Generation ◽  
Pediatric Brain ◽  
Generation Sequencing

Abstract Brain tumors are the leading cause of death in children. Establishing an accurate diagnosis and therapy is critical for patient management. This study evaluated the clinical utility of GlioSeq, a next-generation sequencing (NGS) assay, for the diagnosis and management of pediatric and young adult patients with brain tumors. Between May 2015 and March 2017, 142 consecutive brain tumors were tested using GlioSeq v1 and subset using GlioSeq v2. Out of 142 samples, 63% were resection specimens and 37% were small stereotactic biopsies. GlioSeq sequencing was successful in 100% and 98.6% of the cases for the detection of mutations and copy number changes, and gene fusions, respectively. Average turnaround time was 8.7 days. Clinically significant genetic alterations were detected in 95%, 66.6%, and 66.1% of high-grade gliomas, medulloblastomas, and low-grade gliomas, respectively. GlioSeq enabled molecular-based stratification in 92 (65%) cases by specific molecular subtype assignment (70, 76.1%), substantiating a neuropathologic diagnosis (18, 19.6%), and diagnostic recategorization (4, 4.3%). Fifty-seven percent of the cases harbored therapeutically actionable findings. GlioSeq NGS analysis offers rapid detection of a wide range of genetic alterations across a spectrum of pediatric brain tumors using formalin-fixed, paraffin-embedded specimens and facilitates integrated molecular-morphologic classification and personalized management of pediatric brain tumors.

scholarly journals TMOD-02. GEBTO: GENETICALLY ENGINEERED BRAIN TUMOR ORGANOIDS AS A NOVEL PRECLINICAL MODEL

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i35-i36
Author(s):  
Jens Bunt ◽  
Mieke Roosen ◽  
Evie Egelmeers ◽  
Joris Maas ◽  
Zelda Ode ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Tumor Biology ◽  
Embryonic Stem ◽  
Pediatric Brain Tumors ◽  
Genetically Engineered ◽  
Preclinical Model ◽  
Cells Of Origin ◽  
Pediatric Brain ◽  
Tumor Organoids

Abstract Background One of the bottlenecks in basic and translational research on pediatric brain tumors, is the lack of suitable and representative preclinical models to study tumor biology and drug sensitivity. Over the last decades, extensive molecular characterization has uncovered many entities and subgroups with their unique oncodriving events. However, this heterogeneity is currently not reflected in the models available, especially not for in vitro models. Objectives We aim to generate genetically engineered brain tumor organoids (GEBTO) to represent the molecular variety of embryonal brain tumors and ependymomas. Method Human brain organoids derived from embryonic stem cells are generated to represent the region of tumor origin. To mimic oncodriving events, DNA plasmids are introduced via electroporation in the organoid cells to knockout tumor suppressor genes or overexpress oncogenes. Results Cerebellar and cerebral forebrain organoids were generated as the tissue of origin for medulloblastoma and supratentorial ependymoma (ST-EPN), respectively. Based on the detection of GFP protein encoded by DNA plasmids, the organoid cells can be manipulated within a wide developmental window, which corresponds with the presence of the proposed cells of origin. Different oncodrivers and combinations thereof are now being tested to see whether they result in ectopic growth in cerebral or cerebellar organoids. When successful, the GEBTOs are histologically and molecularly characterized using (single cell) transcriptomic and epigenomic analyses to see how well they resemble human tumors. Discussion Although further development is required, GEBTOs provide a novel avenue to model especially rare pediatric brain tumors, for which tissue and therefore patient-derived models are limited. It also allows for in-depth analyses of the potential cells of origin and the contribution of different mutations to tumor biology.

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