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      Chromosomal instability in adult-type diffuse gliomas

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          Abstract

          Chromosomal instability (CIN) is a fundamental property of cancer and a key underlying mechanism of tumorigenesis and malignant progression, and has been documented in a wide variety of cancers, including colorectal carcinoma with mutations in genes such as APC. Recent reports have demonstrated that CIN, driven in part by mutations in genes maintaining overall genomic stability, is found in subsets of adult-type diffusely infiltrating gliomas of all histologic and molecular grades, with resulting elevated overall copy number burden, chromothripsis, and poor clinical outcome. Still, relatively few studies have examined the effect of this process, due in part to the difficulty of routinely measuring CIN clinically. Herein, we review the underlying mechanisms of CIN, the relationship between chromosomal instability and malignancy, the prognostic significance and treatment potential in various cancers, systemic disease, and more specifically, in diffusely infiltrating glioma subtypes. While still in the early stages of discovery compared to other solid tumor types in which CIN is a known driver of malignancy, the presence of CIN as an early factor in gliomas may in part explain the ability of these tumors to develop resistance to standard therapy, while also providing a potential molecular target for future therapies.

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          The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary.

          The 2016 World Health Organization Classification of Tumors of the Central Nervous System is both a conceptual and practical advance over its 2007 predecessor. For the first time, the WHO classification of CNS tumors uses molecular parameters in addition to histology to define many tumor entities, thus formulating a concept for how CNS tumor diagnoses should be structured in the molecular era. As such, the 2016 CNS WHO presents major restructuring of the diffuse gliomas, medulloblastomas and other embryonal tumors, and incorporates new entities that are defined by both histology and molecular features, including glioblastoma, IDH-wildtype and glioblastoma, IDH-mutant; diffuse midline glioma, H3 K27M-mutant; RELA fusion-positive ependymoma; medulloblastoma, WNT-activated and medulloblastoma, SHH-activated; and embryonal tumour with multilayered rosettes, C19MC-altered. The 2016 edition has added newly recognized neoplasms, and has deleted some entities, variants and patterns that no longer have diagnostic and/or biological relevance. Other notable changes include the addition of brain invasion as a criterion for atypical meningioma and the introduction of a soft tissue-type grading system for the now combined entity of solitary fibrous tumor / hemangiopericytoma-a departure from the manner by which other CNS tumors are graded. Overall, it is hoped that the 2016 CNS WHO will facilitate clinical, experimental and epidemiological studies that will lead to improvements in the lives of patients with brain tumors.
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            The 2021 WHO Classification of Tumors of the Central Nervous System: a summary

            The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, is the sixth version of the international standard for the classification of brain and spinal cord tumors. Building on the 2016 updated fourth edition and the work of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy, the 2021 fifth edition introduces major changes that advance the role of molecular diagnostics in CNS tumor classification. At the same time, it remains wedded to other established approaches to tumor diagnosis such as histology and immunohistochemistry. In doing so, the fifth edition establishes some different approaches to both CNS tumor nomenclature and grading and it emphasizes the importance of integrated diagnoses and layered reports. New tumor types and subtypes are introduced, some based on novel diagnostic technologies such as DNA methylome profiling. The present review summarizes the major general changes in the 2021 fifth edition classification and the specific changes in each taxonomic category. It is hoped that this summary provides an overview to facilitate more in-depth exploration of the entire fifth edition of the WHO Classification of Tumors of the Central Nervous System.
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              Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma.

              Human cancers are complex ecosystems composed of cells with distinct phenotypes, genotypes, and epigenetic states, but current models do not adequately reflect tumor composition in patients. We used single-cell RNA sequencing (RNA-seq) to profile 430 cells from five primary glioblastomas, which we found to be inherently variable in their expression of diverse transcriptional programs related to oncogenic signaling, proliferation, complement/immune response, and hypoxia. We also observed a continuum of stemness-related expression states that enabled us to identify putative regulators of stemness in vivo. Finally, we show that established glioblastoma subtype classifiers are variably expressed across individual cells within a tumor and demonstrate the potential prognostic implications of such intratumoral heterogeneity. Thus, we reveal previously unappreciated heterogeneity in diverse regulatory programs central to glioblastoma biology, prognosis, and therapy. Copyright © 2014, American Association for the Advancement of Science.
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                Author and article information

                Contributors
                timothy.richardson@mountsinai.org
                jamie.walker@mountsinai.org
                abdullahkg@upmc.edu
                samuel.mcbrayer@utsouthwestern.edu
                viapianm@upstate.edu
                zarmeen.mussa@mountsinai.org
                nadejda.tsankova@mountsinai.org
                matija.snuderl@nyulangone.org
                kimmo.hatanpaa@utsouthwestern.edu
                Journal
                Acta Neuropathol Commun
                Acta Neuropathol Commun
                Acta Neuropathologica Communications
                BioMed Central (London )
                2051-5960
                17 August 2022
                17 August 2022
                2022
                : 10
                : 115
                Affiliations
                [1 ]GRID grid.59734.3c, ISNI 0000 0001 0670 2351, Department of Pathology, Molecular, and Cell-Based Medicine, , Icahn School of Medicine at Mount Sinai, ; Annenberg Building, 15th Floor, 1468 Madison Avenue, New York, NY 10029 USA
                [2 ]GRID grid.59734.3c, ISNI 0000 0001 0670 2351, Department of Neuroscience, , Icahn School of Medicine at Mount Sinai, ; New York, NY 10029 USA
                [3 ]GRID grid.21925.3d, ISNI 0000 0004 1936 9000, Department of Neurosurgery, , University of Pittsburgh School of Medicine, ; 200 Lothrop St, Pittsburgh, PA 15213 USA
                [4 ]GRID grid.412689.0, ISNI 0000 0001 0650 7433, Hillman Comprehensive Cancer Center, , University of Pittsburgh Medical Center, ; 5115 Centre Ave, Pittsburgh, PA 15232 USA
                [5 ]GRID grid.267313.2, ISNI 0000 0000 9482 7121, Simmons Comprehensive Cancer Center, , University of Texas Southwestern Medical Center, ; Dallas, TX 75390 USA
                [6 ]GRID grid.267313.2, ISNI 0000 0000 9482 7121, Children’s Medical Center Research Institute, , University of Texas Southwestern Medical Center, ; Dallas, TX 75390 USA
                [7 ]GRID grid.411023.5, ISNI 0000 0000 9159 4457, Department of Neuroscience and Physiology, , State University of New York, Upstate Medical University, ; Syracuse, NY 13210 USA
                [8 ]GRID grid.411023.5, ISNI 0000 0000 9159 4457, Department of Neurosurgery, , State University of New York, Upstate Medical University, ; Syracuse, NY 13210 USA
                [9 ]GRID grid.137628.9, ISNI 0000 0004 1936 8753, Department of Pathology, , New York University Langone Health, ; New York City, NY 10016 USA
                [10 ]GRID grid.267313.2, ISNI 0000 0000 9482 7121, Department of Pathology, , University of Texas Southwestern Medical Center, ; Dallas, TX 75390 USA
                Author information
                http://orcid.org/0000-0001-7068-5517
                Article
                1420
                10.1186/s40478-022-01420-w
                9386991
                35978439
                eafe9427-88ed-47a4-b3c3-797b5fae3ed8
                © The Author(s) 2022

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 12 July 2022
                : 4 August 2022
                Funding
                Funded by: NINDS
                Award ID: R01NS106229
                Award Recipient :
                Funded by: NIDA
                Award ID: RF1DA048810
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100017655, Friedberg Charitable Foundation;
                Funded by: FundRef http://dx.doi.org/10.13039/100018864, Making Headway Foundation;
                Categories
                Review
                Custom metadata
                © The Author(s) 2022

                glioma,astrocytoma,oligodendroglioma,glioblastoma,chromothripsis,chromosomal instability,cin,copy number burden,copy number variation

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