scholarly journals Genetic Architectures and Cell-of-Origin in Glioblastoma

2021 ◽  
Vol 10 ◽  
Author(s):  
Hyun Jung Kim ◽  
Jung Won Park ◽  
Jeong Ho Lee
Keyword(s):  
Brain Cancer ◽  
Somatic Mutations ◽  
Driver Mutations ◽  
Fundamental Issue ◽  
Cell Of Origin ◽  
Cellular Origin ◽  
Common Cancer ◽  
The Central Nervous System ◽  
Glial Precursor ◽  
Novel Therapeutic

An aggressive primary brain cancer, glioblastoma (GBM) is the most common cancer of the central nervous system in adults. However, an inability to identify its cell-of-origin has been a fundamental issue hindering further understanding of the nature and pathogenesis of GBM, as well as the development of novel therapeutic targets. Researchers have hypothesized that GBM arises from an accumulation of somatic mutations in neural stem cells (NSCs) and glial precursor cells that confer selective growth advantages, resulting in uncontrolled proliferation. In this review, we outline genomic perspectives on IDH-wildtype and IDH-mutant GBMs pathogenesis and the cell-of-origin harboring GBM driver mutations proposed by various GBM animal models. Additionally, we discuss the distinct neurodevelopmental programs observed in either IDH-wildtype or IDH-mutant GBMs. Further research into the cellular origin and lineage hierarchy of GBM will help with understanding the evolution of GBMs and with developing effective targets for treating GBM cancer cells.

scholarly journals GEN-13 FIREWORK PATTERN OF CANCER GENESIS FOR GLIOBLASTOMA, IDH-WILDTYPE

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii8-ii8
Author(s):  
Seon-Jin Yoon ◽  
Junseong Park ◽  
Hyun Jung Kim ◽  
Joo Ho Lee ◽  
Jong Hee Chang ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Subventricular Zone ◽  
Therapeutic Target ◽  
Somatic Mutations ◽  
Cancer Tissue ◽  
Cell Of Origin ◽  
History Of ◽  
The Central Nervous System ◽  
Special Environment

Abstract Treatment of Glioblastoma (GBM), IDH-wildtype is a history of sequential failure. The cure for this disease is a distant story, and it is really the emperor of cancer. We believe that GBM should not be considered one of several cancers, and GBM is a cancer that occurs in a special environment called the central nervous system (CNS). What is the biggest difference between other cancers and cancers of the nervous system? It is thought to be neurogenesis. This presentation will review GBM genesis based on neurogensis of CNS. It also explains what the cell of origin is, what somatic mutations occur at the cell of origin, and why these somatic mutations occur. Human glioblastoma (GBM) occurs in a place without cancer tissue, that is, in the subventricular zone and have introduced the name of the firework pattern of cancer genesis, which is a metaphorical representation of the GBM genesis. So far, we have been trying to develop therapeutics focused on bulk tumors. However, in the case of GBM, IDH-wildtype, it has been found that the cell of origin is not in the tumor but is in normal SVZ, so it is now considered that the therapeutic target should also include the cell of origin.

scholarly journals Genomic Landscape of Intramedullary Spinal Cord Gliomas

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ming Zhang ◽  
Rajiv R. Iyer ◽  
Tej D. Azad ◽  
Qing Wang ◽  
Tomas Garzon-Muvdi ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Genetic Basis ◽  
Somatic Mutations ◽  
Treatment Options ◽  
Driver Mutations ◽  
Spinal Cord Tumors ◽  
Intramedullary Spinal Cord ◽  
Whole Exome ◽  
Genomic Landscape ◽  
The Central Nervous System

AbstractIntramedullary spinal cord tumors (IMSCTs) are rare neoplasms that have limited treatment options and are associated with high rates of morbidity and mortality. To better understand the genetic basis of these tumors we performed whole exome sequencing on 45 tumors and matched germline DNA, including twenty-nine spinal cord ependymomas and sixteen astrocytomas. Though recurrent somatic mutations in IMSCTs were rare, we identified NF2 mutations in 15.7% of tumors (ependymoma, N = 7; astrocytoma, N = 1), RP1 mutations in 5.9% of tumors (ependymoma, N = 3), and ESX1 mutations in 5.9% of tumors (ependymoma, N = 3). We further identified copy number amplifications in CTU1 in 25% of myxopapillary ependymomas. Given the paucity of somatic driver mutations, we further performed whole-genome sequencing of 12 tumors (ependymoma, N = 9; astrocytoma, N = 3). Overall, we observed that IMSCTs with intracranial histologic counterparts (e.g. glioblastoma) did not harbor the canonical mutations associated with their intracranial counterparts. Our findings suggest that the origin of IMSCTs may be distinct from tumors arising within other compartments of the central nervous system and provides the framework to begin more biologically based therapeutic strategies.

scholarly journals Low immunogenicity of common cancer hot spot mutations resulting in false immunogenic selection signals

PLoS Genetics ◽  
2021 ◽  
Vol 17 (2) ◽  
pp. e1009368
Author(s):  
Arne Claeys ◽  
Tom Luijts ◽  
Kathleen Marchal ◽  
Jimmy Van den Eynden
Keyword(s):  
Somatic Mutations ◽  
Hot Spot ◽  
Selective Advantage ◽  
Driver Mutations ◽  
Virtual Patients ◽  
High Frequencies ◽  
Fitness Advantage ◽  
Common Cancer ◽  
Selection Processes ◽  
Genotype Variation

Cancer is driven by somatic mutations that result in a cellular fitness advantage. This selective advantage is expected to be counterbalanced by the immune system when these driver mutations simultaneously lead to the generation of neoantigens, novel peptides that are presented at the cancer cell membrane via HLA molecules from the MHC complex. The presentability of these peptides is determined by a patient’s MHC genotype and it has been suggested that this results in MHC genotype-specific restrictions of the oncogenic mutational landscape. Here, we generated a set of virtual patients, each with an identical and prototypical MHC genotype, and show that the earlier reported HLA affinity differences between observed and unobserved mutations are unrelated to MHC genotype variation. We demonstrate how these differences are secondary to high frequencies of 13 hot spot driver mutations in 6 different genes. Several oncogenic mechanisms were identified that lower the peptides’ HLA affinity, including phospho-mimicking substitutions in BRAF, destabilizing tyrosine mutations in TP53 and glycine-rich mutational contexts in the GTP-binding KRAS domain. In line with our earlier findings, our results emphasize that HLA affinity predictions are easily misinterpreted when studying immunogenic selection processes.

scholarly journals Exomic Sequencing of Medullary Thyroid Cancer Reveals Dominant and Mutually Exclusive Oncogenic Mutations in RET and RAS

2013 ◽  
Vol 98 (2) ◽  
pp. E364-E369 ◽  
Author(s):  
Nishant Agrawal ◽  
Yuchen Jiao ◽  
Mark Sausen ◽  
Rebecca Leary ◽  
Chetan Bettegowda ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Somatic Mutations ◽  
Medullary Thyroid Cancer ◽  
Driver Mutations ◽  
High Confidence ◽  
Kras Mutations ◽  
Protein Coding ◽  
Medullary Thyroid ◽  
Oncogenic Mutations ◽  
Independent Cohort

Abstract Context: Medullary thyroid cancer (MTC) is a rare thyroid cancer that can occur sporadically or as part of a hereditary syndrome. Objective: To explore the genetic origin of MTC, we sequenced the protein coding exons of approximately 21,000 genes in 17 sporadic MTCs. Patients and Design: We sequenced the exomes of 17 sporadic MTCs and validated the frequency of all recurrently mutated genes and other genes of interest in an independent cohort of 40 MTCs comprised of both sporadic and hereditary MTC. Results: We discovered 305 high-confidence mutations in the 17 sporadic MTCs in the discovery phase, or approximately 17.9 somatic mutations per tumor. Mutations in RET, HRAS, and KRAS genes were identified as the principal driver mutations in MTC. All of the other additional somatic mutations, including mutations in spliceosome and DNA repair pathways, were not recurrent in additional tumors. Tumors without RET, HRAS, or KRAS mutations appeared to have significantly fewer mutations overall in protein coding exons. Conclusions: Approximately 90% of MTCs had mutually exclusive mutations in RET, HRAS, and KRAS, suggesting that RET and RAS are the predominant driver pathways in MTC. Relatively few mutations overall and no commonly recurrent driver mutations other than RET, HRAS, and KRAS were seen in the MTC exome.

scholarly journals Clonal approaches to understanding the impact of mutations on hematologic disease development

Blood ◽  
2019 ◽  
Vol 133 (13) ◽  
pp. 1436-1445 ◽  
Author(s):  
Jyoti Nangalia ◽  
Emily Mitchell ◽  
Anthony R. Green
Keyword(s):  
Somatic Mutations ◽  
Clonal Selection ◽  
Single Cells ◽  
Driver Mutations ◽  
Great Promise ◽  
Tumor Evolution ◽  
Disease Development ◽  
Hematopoietic Tissue ◽  
The Impact

Abstract Interrogation of hematopoietic tissue at the clonal level has a rich history spanning over 50 years, and has provided critical insights into both normal and malignant hematopoiesis. Characterization of chromosomes identified some of the first genetic links to cancer with the discovery of chromosomal translocations in association with many hematological neoplasms. The unique accessibility of hematopoietic tissue and the ability to clonally expand hematopoietic progenitors in vitro has provided fundamental insights into the cellular hierarchy of normal hematopoiesis, as well as the functional impact of driver mutations in disease. Transplantation assays in murine models have enabled cellular assessment of the functional consequences of somatic mutations in vivo. Most recently, next-generation sequencing–based assays have shown great promise in allowing multi-“omic” characterization of single cells. Here, we review how clonal approaches have advanced our understanding of disease development, focusing on the acquisition of somatic mutations, clonal selection, driver mutation cooperation, and tumor evolution.

scholarly journals MODL-21. INTEGRATIVE APPROACHES IN FUNCTIONAL GENOMICS TO IDENTIFY GENETIC DEPENDENCIES IN PEDIATRIC BRAIN CANCER

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii415-iii415
Author(s):  
Claire Sun ◽  
Caroline Drinkwater ◽  
Dhanya Sooraj ◽  
Gabrielle Bradshaw ◽  
Claire Shi ◽  
...  
Keyword(s):  
Functional Genomics ◽  
Precision Medicine ◽  
Brain Cancer ◽  
Human Genomes ◽  
Pediatric Cancer Patients ◽  
Crispr Screen ◽  
The Central Nervous System ◽  
Molecular Aberrations ◽  
Genetic Profiles ◽  
Pediatric Brain

Abstract The precise decoding of human genomes facilitated by the advancements in next-generation sequencing has led to a better understanding of genetic underpinnings of pediatric brain cancers. Indeed, it is now evident that tumours of the same type harbour distinct driving mutations and molecular aberrations that can result in different prognosis and treatment outcomes. The profounder insight into the the identity, amount and types of molecular aberrations has paved the way for the advent of targeted therapies in precision medicine. Nevertheless, less than 10% of pediatric cancer patients harbour actionable mutations. Strictly limited therapeutic options that are firstly available for brain cancers and secondly acceptable for children’s development further impede the breakthrough in the survival rate in pediatric brain cancers. This underscores a desperate need to delve beyond genomic sequencing to identify biomarker coupled therapies that not only featured with treatment efficacy in the central nervous system but also acceptable side effects for children. The Hudson-Monash Paediatric Precision Medicine (HMPPM) Program focuses on utilising genetic profiles of patients’ tumour models to identify new therapeutic targets and repurpose existing ones using high-throughput functional genomics screens (2220 drugs and CRISPR screen of 300 oncogenic genes). Using a large compendium of over sixty patient derived paediatric brain cancer models, we provide proof-of-concept data that shows an integrative pipeline for functional genomics with multi-omics datasets to perform genotype-phenotype correlations and, therefore, identify genetic dependencies. Herein, using several examples in ATRT, DIPG and HGG, we show how functional interrogations can better define molecular subclassification of tumours and identify unique vulnerabilities.

scholarly journals Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors

2018 ◽  
Vol 116 (2) ◽  
pp. 619-624 ◽  
Author(s):  
Charles Li ◽  
Elena Bonazzoli ◽  
Stefania Bellone ◽  
Jungmin Choi ◽  
Weilai Dong ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Somatic Mutations ◽  
Driver Mutations ◽  
Cancer Evolution ◽  
Metastatic Tumors ◽  
Driver Genes ◽  
Primary Tumors ◽  
Mutational Landscape ◽  
Recurrent Tumors ◽  
Bet Inhibitors

Ovarian cancer remains the most lethal gynecologic malignancy. We analyzed the mutational landscape of 64 primary, 41 metastatic, and 17 recurrent fresh-frozen tumors from 77 patients along with matched normal DNA, by whole-exome sequencing (WES). We also sequenced 13 pairs of synchronous bilateral ovarian cancer (SBOC) to evaluate the evolutionary history. Lastly, to search for therapeutic targets, we evaluated the activity of the Bromodomain and Extra-Terminal motif (BET) inhibitor GS-626510 on primary tumors and xenografts harboring c-MYC amplifications. In line with previous studies, the large majority of germline and somatic mutations were found in BRCA1/2 (21%) and TP53 (86%) genes, respectively. Among mutations in known cancer driver genes, 77% were transmitted from primary tumors to metastatic tumors, and 80% from primary to recurrent tumors, indicating that driver mutations are commonly retained during ovarian cancer evolution. Importantly, the number, mutation spectra, and signatures in matched primary–metastatic tumors were extremely similar, suggesting transcoelomic metastases as an early dissemination process using preexisting metastatic ability rather than an evolution model. Similarly, comparison of SBOC showed extensive sharing of somatic mutations, unequivocally indicating a common ancestry in all cases. Among the 17 patients with matched tumors, four patients gained PIK3CA amplifications and two patients gained c-MYC amplifications in the recurrent tumors, with no loss of amplification or gain of deletions. Primary cell lines and xenografts derived from chemotherapy-resistant tumors demonstrated sensitivity to JQ1 and GS-626510 (P = 0.01), suggesting that oral BET inhibitors represent a class of personalized therapeutics in patients harboring recurrent/chemotherapy-resistant disease.

scholarly journals Nucleotide excision repair is impaired by binding of transcription factors to DNA

2015 ◽  
Author(s):  
Radhakrishnan Sabarinathan ◽  
Loris Mularoni ◽  
Jordi Deu-Pons ◽  
Abel Gonzalez-Perez ◽  
Nuria Lopez-Bigas
Keyword(s):  
Nucleotide Excision Repair ◽  
Mutation Rate ◽  
Binding Sites ◽  
Somatic Mutations ◽  
Excision Repair ◽  
Replication Timing ◽  
Driver Mutations ◽  
Cancer Driver ◽  
Nucleotide Excision ◽  
Active Transcription

Somatic mutations are the driving force of cancer genome evolution. The rate of somatic mutations appears in great variability across the genome due to chromatin organization, DNA accessibility and replication timing. However, other variables that may influence the mutation rate locally, such as DNA-binding proteins, are unknown. Here we demonstrate that the rate of somatic mutations in melanoma tumors is highly increased at active Transcription Factor binding sites (TFBS) and nucleosome embedded DNA, compared to their flanking regions. Using recently available excision-repair sequencing (XR-seq) data, we show that the higher mutation rate at these sites is caused by a decrease of the levels of nucleotide excision repair (NER) activity. Therefore, our work demonstrates that DNA-bound proteins interfere with the NER machinery, which results in an increased rate of mutations at their binding sites. This finding has important implications in our understanding of mutational and DNA repair processes and in the identification of cancer driver mutations.

Some fly sensory organs are gliogenic and require glide/gcm in a precursor that divides symmetrically and produces glial cells

Development ◽  
2000 ◽  
Vol 127 (17) ◽  
pp. 3735-3743 ◽  
Author(s):  
V. Van De Bor ◽  
R. Walther ◽  
A. Giangrande
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Peripheral Nervous System ◽  
Glial Cell ◽  
Glial Cells ◽  
Sensory Organ ◽  
Asymmetric Distribution ◽  
Sensory Organs ◽  
The Central Nervous System ◽  
Glial Precursor

In flies, the choice between neuronal and glial fates depends on the asymmetric division of multipotent precursors, the neuroglioblast of the central nervous system and the IIb precursor of the sensory organ lineage. In the central nervous system, the choice between the two fates requires asymmetric distribution of the glial cell deficient/glial cell missing (glide/gcm) RNA in the neuroglioblast. Preferential accumulation of the transcript in one of the daughter cells results in the activation of the glial fate in that cell, which becomes a glial precursor. Here we show that glide/gcm is necessary to induce glial differentiation in the peripheral nervous system. We also present evidence that glide/gcm RNA is not necessary to induce the fate choice in the peripheral multipotent precursor. Indeed, glide/gcm RNA and protein are first detected in one daughter of IIb but not in IIb itself. Thus, glide/gcm is required in both central and peripheral glial cells, but its regulation is context dependent. Strikingly, we have found that only subsets of sensory organs are gliogenic and express glide/gcm. The ability to produce glial cells depends on fixed, lineage related, cues and not on stochastic decisions. Finally, we show that after glide/gcm expression has ceased, the IIb daughter migrates and divides symmetrically to produce several mature glial cells. Thus, the glide/gcm-expressing cell, also called the fifth cell of the sensory organ, is indeed a glial precursor. This is the first reported case of symmetric division in the sensory organ lineage. These data indicate that the organization of the fly peripheral nervous system is more complex than previously thought.

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