Transcription Profiling of Brain Tumors: Tumor Biology and Treatment Stratification

CNS Cancer ◽  
2009 ◽  
pp. 529-551 ◽  
Author(s):  
Erik P. Sulman ◽  
Marisol Guerrero ◽  
Ken Aldape
Keyword(s):  
Brain Tumors ◽  
Tumor Biology ◽  
Transcription Profiling

Epigenetics in Clinical Management of Children and Adolescents with Brain Tumors

2017 ◽  
Vol 18 (1) ◽  
pp. 57-64 ◽  
Author(s):  
Andres Morales La Madrid ◽  
Mark W. Kieran
Keyword(s):  
Nervous System ◽  
Brain Tumors ◽  
Children And Adolescents ◽  
Tumor Biology ◽  
Tumor Development ◽  
Integrated Approach ◽  
Cell Types ◽  
Pediatric Brain Tumors ◽  
Tumor Formation ◽  
Molecular Profile

Central nervous system (CNS) tumors represent the second most prevalent group of cancers in children and adolescents, yet account for the majority of childhood cancer-related deaths and considerable morbidity among survivors, due to high-intensity non-selective standard therapies delivered to immature nervous system structures undergoing development. These tumors arise at different ages –not infrequently very early in life-, in different locations and cellular contexts, have varied cell types of origin, and have heterogeneous responses to the “classic” current therapeutic approaches. Demographic, radiologic and morphological characterization have several limitations, putting into the “classic boxes” heterogeneous tumors that are diverse in their genetic and epigenetic background and that will likely behave biologically different. Given that, epigenetic disruption (i.e. DNA methylation, histone modification and chromatin remodeling) is a common feature identified more and more frequently in pediatric cancer, it is logical to speculate that interrogating epigenetic marks may help to further define the molecular profile, and therefore tumor biology, evolution and treatment of these tumors. An integrated approach that incorporates traditional features complemented with genetic and epigenenetic specific markers offers tremendous promise to “risk-group” stratification and better prognostication. Also, it will help unveil the key driver pathways for tumor formation and for the discovery of targeted therapy for neoplasms that appear in the developing brain, facilitating early identification of therapy responders and track accurately disease progression. In this paper, we reviewed the most representative pediatric brain tumors where epigenetic alterations have been identified as initiating or driving events in tumor development, maintenance or progression.

scholarly journals Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 10 ◽  
Author(s):  
Pamela Bielli ◽  
Vittoria Pagliarini ◽  
Marco Pieraccioli ◽  
Cinzia Caggiano ◽  
Claudio Sette
Keyword(s):  
Alternative Splicing ◽  
Brain Tumors ◽  
Current Knowledge ◽  
Tumor Biology ◽  
Cancer Therapies ◽  
Cellular Processes ◽  
Genes Encoding ◽  
Targeted Cancer Therapies ◽  
Oncogenic Driver ◽  
Intercellular Communications

Brain tumors are a heterogeneous group of neoplasms ranging from almost benign to highly aggressive phenotypes. The malignancy of these tumors mostly relies on gene expression reprogramming, which is frequently accompanied by the aberrant regulation of RNA processing mechanisms. In brain tumors, defects in alternative splicing result either from the dysregulation of expression and activity of splicing factors, or from mutations in the genes encoding splicing machinery components. Aberrant splicing regulation can generate dysfunctional proteins that lead to modification of fundamental physiological cellular processes, thus contributing to the development or progression of brain tumors. Herein, we summarize the current knowledge on splicing abnormalities in brain tumors and how these alterations contribute to the disease by sustaining proliferative signaling, escaping growth suppressors, or establishing a tumor microenvironment that fosters angiogenesis and intercellular communications. Lastly, we review recent efforts aimed at developing novel splicing-targeted cancer therapies, which employ oligonucleotide-based approaches or chemical modulators of alternative splicing that elicit an impact on brain tumor biology.

scholarly journals Metabolic Landscape of a Genetically Engineered Mouse Model of IDH1 Mutant Glioma

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1633 ◽  
Author(s):  
Victor Ruiz-Rodado ◽  
Tomohiro Seki ◽  
Tyrone Dowdy ◽  
Adrian Lita ◽  
Meili Zhang ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Mouse Model ◽  
Tumor Biology ◽  
Central Carbon Metabolism ◽  
Idh1 Mutation ◽  
Genetically Engineered ◽  
Metabolic Reprogramming ◽  
Imaging Biomarkers ◽  
Isocitrate Dehydrogenase 1 ◽  
Genetically Engineered Mouse Model

Understanding the metabolic reprogramming of aggressive brain tumors has potential applications for therapeutics as well as imaging biomarkers. However, little is known about the nutrient requirements of isocitrate dehydrogenase 1 (IDH1) mutant gliomas. The IDH1 mutation involves the acquisition of a neomorphic enzymatic activity which generates D-2-hydroxyglutarate from α-ketoglutarate. In order to gain insight into the metabolism of these malignant brain tumors, we conducted metabolic profiling of the orthotopic tumor and the contralateral regions for the mouse model of IDH1 mutant glioma; as well as to examine the utilization of glucose and glutamine in supplying major metabolic pathways such as glycolysis and tricarboxylic acid (TCA). We also revealed that the main substrate of 2-hydroxyglutarate is glutamine in this model, and how this re-routing impairs its utilization in the TCA. Our 13C tracing analysis, along with hyperpolarized magnetic resonance experiments, revealed an active glycolytic pathway similar in both regions (tumor and contralateral) of the brain. Therefore, we describe the reprogramming of the central carbon metabolism associated with the IDH1 mutation in a genetically engineered mouse model which reflects the tumor biology encountered in glioma patients.

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 The Practical Application of Emerging Technologies Influencing the Diagnosis and Care of Patients With Primary Brain Tumors

2020 ◽  
pp. e35-e46 ◽  
Author(s):  
Leland S. Hu ◽  
Daniel J. Brat ◽  
Orin Bloch ◽  
Shakti Ramkissoon ◽  
Glenn J. Lesser
Keyword(s):  
Brain Tumors ◽  
Surgical Navigation ◽  
Tumor Biology ◽  
Primary Brain Tumors ◽  
Tumor Treating Fields ◽  
Histopathologic Diagnosis ◽  
Therapeutic Decision Making ◽  
Next Generation Sequencing Ngs ◽  
Ngs Data

Over the past decade, a variety of new and innovative technologies has led to important advances in the diagnosis and management of patients with primary malignant brain tumors. New approaches to surgical navigation and tumor localization, advanced imaging to define tumor biology and treatment response, and the widespread adoption of a molecularly defined integrated diagnostic paradigm that complements traditional histopathologic diagnosis continue to impact the day-to-day care of these patients. In the neuro-oncology clinic, discussions with patients about the role of tumor treating fields (TTFields) and the incorporation of next-generation sequencing (NGS) data into therapeutic decision-making are now a standard practice. This article summarizes newer applications of technology influencing the pathologic, neuroimaging, neurosurgical, and medical management of patients with malignant primary brain tumors.

scholarly journals 3D Whole-Brain Imaging Approaches to Study Brain Tumors

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1897
Author(s):  
Julian Taranda ◽  
Sevin Turcan
Keyword(s):  
Brain Tumors ◽  
Ex Vivo ◽  
Tumor Biology ◽  
Three Dimensional ◽  
Light Sheet ◽  
Response To Therapy ◽  
Imaging Modalities ◽  
Two Photon ◽  
Using Data

Although our understanding of the two-dimensional state of brain tumors has greatly expanded, relatively little is known about their spatial structures. The interactions between tumor cells and the tumor microenvironment (TME) occur in a three-dimensional (3D) space. This volumetric distribution is important for elucidating tumor biology and predicting and monitoring response to therapy. While static 2D imaging modalities have been critical to our understanding of these tumors, studies using 3D imaging modalities are needed to understand how malignant cells co-opt the host brain. Here we summarize the preclinical utility of in vivo imaging using two-photon microscopy in brain tumors and present ex vivo approaches (light-sheet fluorescence microscopy and serial two-photon tomography) and highlight their current and potential utility in neuro-oncology using data from solid tumors or pathological brain as examples.

Radiomics, Metabolic, and Molecular MRI for Brain Tumors

2018 ◽  
Vol 38 (01) ◽  
pp. 032-040 ◽  
Author(s):  
Philipp Kickingereder ◽  
Ovidiu Andronesi
Keyword(s):  
Magnetic Resonance ◽  
Brain Tumors ◽  
Imaging Techniques ◽  
Tumor Biology ◽  
Resonance Spectroscopy ◽  
Resonance Imaging ◽  
Tumor Patients ◽  
Monitoring Treatment ◽  
Monitoring Treatment Response

Magnetic resonance imaging plays a key role in diagnosis and treatment monitoring of brain tumors. Novel imaging techniques that specifically interrogate aspects of underlying tumor biology and biochemical pathways have great potential in neuro-oncology. This review focuses on the emerging role of 2-hydroxyglutarate-targeted magnetic resonance spectroscopy, as well as radiomics and radiogenomics in establishing diagnosis for isocitrate dehydrogenase mutant gliomas, and for monitoring treatment response and predicting prognosis of this group of brain tumor patients.

scholarly journals Meta-topologies define distinct anatomical classes of brain tumors linked to histology and survival

2021 ◽  
Author(s):  
Julius M Kernbach ◽  
Daniel Delev ◽  
Georg Neuloh ◽  
Hans Clusmann ◽  
Danilo Bzdok ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Clinical Decision Making ◽  
Learning Algorithm ◽  
Tumor Biology ◽  
Clinical Information ◽  
Clinical Decision ◽  
Fine Grained ◽  
Molecular Features ◽  
Data Driven Approach

Background The current WHO classification integrates histological and molecular features of brain tumors. The aim of this study was to identify generalizable topological patterns with the potential to add an anatomical dimension to the classification of brain tumors. Methods We applied non-negative matrix factorization as an unsupervised pattern discovery strategy to the fine-grained topographic tumor profiles of 936 patients with primary and secondary brain tumors. From the anatomical features alone, this machine learning algorithm enabled the extraction of latent topological tumor patterns, termed meta-topologies. The optimal parts-based representation was automatically determined in 10,000 split-half iterations. We further characterized each meta-topologys unique histopathologic profile and survival probability, thus linking important biological and clinical information to the underlying anatomical patterns Results In primary brain tumors, six meta-topologies were extracted, each detailing a transpallial pattern with distinct parenchymal and ventricular compositions. We identified one infratentorial, one allopallial, three neopallial (parieto-occipital, frontal, temporal) and one unisegmental meta-topology. Each meta-topology mapped to distinct histopathologic and molecular profiles. The unisegmental meta-topology showed the strongest anatomical-clinical link demonstrating a survival advantage in histologically identical tumors. Brain metastases separated to an infra- and supratentorial meta-topology with anatomical patterns highlighting their affinity to the cortico-subcortical boundary of arterial watershed areas. Conclusions Using a novel data-driven approach, we identified generalizable topological patterns in both primary and secondary brain tumors Differences in the histopathologic profiles and prognosis of these anatomical tumor classes provide insights into the heterogeneity of tumor biology and might add to personalized clinical decision making.

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.

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