17
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      LONGITUDINAL MOLECULAR TRAJECTORIES OF DIFFUSE GLIOMA IN ADULTS

      research-article
      The Glioma Longitudinal Analysis (GLASS) Consortium, 1 , 2 , 54 , 1 , 54 , 1 , 1 , 3 , 1 , 4 , 1 , 1 , 5 , 6 , 7 , 8 , 1 , 9 , 10 , 11 , 12 , 10 , 11 , 7 , 13 , 14 , 15 , 16 , 3 , 17 , 18 , 19 , 1 , 20 , 21 , 22 , 23 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 24 , 33 , 18 , 16 , 34 , 1 , 2 , 23 , 1 , 26 , 10 , 11 , 23 , 35 , 24 , 36 , 24 , 37 , 14 , 38 , 1 , 39 , 2 , 35 , 1 , 40 , 41 , 35 , 33 , 26 , 6 , 42 , 43 , 7 , 14 , 3 , 27 , 44 , 27 , 45 , 46 , 47 , 48 , 49 , 2 , 50 , 2 , 51 , 52 , 6 , 53 , GLASS Consortium, 6 , 6 , 3 , 1 , ¥
      Nature

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear 1, 2 . Here, we analyzed temporally separated DNA sequencing data and matched clinical annotation from 222 patients with glioma. Through mutational and copy number analyses across the three major subtypes of diffuse glioma, we observed that driver genes detected at initial disease were retained at recurrence, while there was little evidence of recurrence-specific gene alterations. Treatment with alkylating-agents resulted in a hypermutator phenotype at different rates across glioma subtypes, and hypermutation was not associated with differences in survival. Acquired aneuploidy was frequently detected in recurrent gliomas characterized by presence of an IDH mutation but without 1p/19q codeletion and further converged with acquired cell cycle alterations and poor outcomes. We show that the clonal architecture of each tumor remains similar over time and that absence of clonal selection was associated with increased survival. Finally, we did not observe differences in immunoediting levels between initial and recurrent glioma. Our results collectively argue that the strongest selective pressures occur early during glioma development and that current therapies shape this evolution in a largely stochastic manner.

          Related collections

          Most cited references15

          • Record: found
          • Abstract: found
          • Article: not found

          Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial

          Neoantigens, which are derived from tumour-specific protein-coding mutations, are exempt from central tolerance, can generate robust immune responses1,2 and can function as bona fide antigens that facilitate tumour rejection3. Here we demonstrate that a strategy that uses multi-epitope, personalized neoantigen vaccination, which has previously been tested in patients with high-risk melanoma4-6, is feasible for tumours such as glioblastoma, which typically have a relatively low mutation load1,7 and an immunologically 'cold' tumour microenvironment8. We used personalized neoantigen-targeting vaccines to immunize patients newly diagnosed with glioblastoma following surgical resection and conventional radiotherapy in a phase I/Ib study. Patients who did not receive dexamethasone-a highly potent corticosteroid that is frequently prescribed to treat cerebral oedema in patients with glioblastoma-generated circulating polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses that were enriched in a memory phenotype and showed an increase in the number of tumour-infiltrating T cells. Using single-cell T cell receptor analysis, we provide evidence that neoantigen-specific T cells from the peripheral blood can migrate into an intracranial glioblastoma tumour. Neoantigen-targeting vaccines thus have the potential to favourably alter the immune milieu of glioblastoma.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: found

            Neoantigen-directed immune escape in lung cancer evolution

            The interplay between an evolving cancer and the dynamic immune-microenvironment remains unclear. Here, we analyze 258 regions from 88 early-stage untreated non-small cell lung cancers (NSCLCs) using RNAseq and pathology tumor infiltrating lymphocyte estimates. The immune-microenvironment was variable both between and within patients’ tumors. Diverse immune selection pressures were associated with different mechanisms of neoantigen presentation dysfunction restricted to distinct microenvironments. Sparsely infiltrated tumors exhibited evidence for historical immunoediting, with a waning of neoantigen-editing during tumor evolution, or copy number loss of historically clonal neoantigens. Immune-infiltrated tumor regions exhibited ongoing immunoediting, with either HLA LOH or depletion of expressed neoantigens. Promoter hypermethylation of genes harboring neoantigens was identified as an epigenetic mechanism of immunoediting. Our results suggest the immune-microenvironment exerts a strong selection pressure in early stage, untreated NSCLCs, producing multiple routes to immune evasion, which are clinically relevant, forecasting poor disease-free survival in multivariate analysis.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma.

              Comprehensive knowledge of the genomic alterations that underlie cancer is a critical foundation for diagnostics, prognostics, and targeted therapeutics. Systematic efforts to analyze cancer genomes are underway, but the analysis is hampered by the lack of a statistical framework to distinguish meaningful events from random background aberrations. Here we describe a systematic method, called Genomic Identification of Significant Targets in Cancer (GISTIC), designed for analyzing chromosomal aberrations in cancer. We use it to study chromosomal aberrations in 141 gliomas and compare the results with two prior studies. Traditional methods highlight hundreds of altered regions with little concordance between studies. The new approach reveals a highly concordant picture involving approximately 35 significant events, including 16-18 broad events near chromosome-arm size and 16-21 focal events. Approximately half of these events correspond to known cancer-related genes, only some of which have been previously tied to glioma. We also show that superimposed broad and focal events may have different biological consequences. Specifically, gliomas with broad amplification of chromosome 7 have properties different from those with overlapping focalEGFR amplification: the broad events act in part through effects on MET and its ligand HGF and correlate with MET dependence in vitro. Our results support the feasibility and utility of systematic characterization of the cancer genome.
                Bookmark

                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                10 October 2019
                20 November 2019
                December 2019
                20 May 2020
                : 576
                : 7785
                : 112-120
                Affiliations
                [1 ]The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA.
                [2 ]Amsterdam UMC, Vrije Universiteit Amsterdam, Departments of Neurology, Neurosurgery, Pathology, Brain Tumor Center Amsterdam, de Boelelaan 1117, Amsterdam, Netherlands
                [3 ]Leeds Institute of Medical Research at St James’s, University of Leeds, LS9 7TF, UK.
                [4 ]DKFZ Division of Translational Neurooncology at the West German Cancer Center, German Cancer Consortium Partner Site & Department of Neurosurgery, University Hospital Essen, 45147 Essen, Germany
                [5 ]National Cancer Institute, Bethesda, MD 20892, USA
                [6 ]Departments of Neuro-Oncology, Neurosurgery, Pathology, Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77031, USA
                [7 ]CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria
                [8 ]1 st Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary
                [9 ]Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, North Carolina 27710, USA
                [10 ]Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA
                [11 ]Broad Institute, 415 Main Street, Cambridge, MA 02142, USA
                [12 ]Department of Population and Quantitative Health Sciences and Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, 2103 Cornell Rd, WRB 2-526, Cleveland, Ohio 44106, USA
                [13 ]Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
                [14 ]Division of Neuro-Oncology, Massachusetts General Hospital, Boston, MA 02114, USA
                [15 ]Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago IL, 60611, USA
                [16 ]University of Liverpool & Walton Centre NHS Trust, Liverpool, L9 7LJ, UK
                [17 ]Division of Neurosurgery, The University of Connecticut Health Center, Farmington, CT, USA
                [18 ]Leeds Teaching Hospital NHS Trust, St James’s University Hospital, Leeds, LS9 7TF, UK
                [19 ]Department of Radiation Oncology, Arthur G. James Hospital/Ohio State Comprehensive Cancer Center, Columbus, OH, 43210, USA
                [20 ]UConn Health, Department of Genetics and Genome Sciences, Farmington, CT, 06030, USA
                [21 ]Yale University School of Public Health, New Haven, CT, 06511, USA
                [22 ]Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA, USA
                [23 ]Departments of Neurology, Pathology, Radiology and Biomedical Engineering, Medical College of Wisconsin, Milwaukee, WI USA
                [24 ]Department of Neurosurgery, University of California San Francisco, CA 94143, USA
                [25 ]Fondazione IRCCS Istituto Neurologico Besta, Milano, Italy
                [26 ]Division of Molecular Genetics, Heidelberg Center for Personalized Oncology, German Cancer Research Consortium, German Cancer Research Center (DKFZ), Heidelberg, Germany
                [27 ]Departments of Neurology, Radiology and Nuclear Medicine, Erasmus MC - University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands
                [28 ]Olivia Newton-John Cancer Research Institute, Austin Health, Melbourne, Australia
                [29 ]La Trobe University School of Cancer Medicine, Heidelberg, Victoria, Australia
                [30 ]Department of Medicine, University of Melbourne, Heidelberg, Victoria, AustraliaNeuro-oncology Branch, National Institutes of Health, Bethesda, Maryland, 20892, USA
                [31 ]Neuro-oncology Branch, National Institutes of Health, Bethesda, Maryland, 20892, USA
                [32 ]Anatomic Pathology Service, Hôpital de l’Enfant-Jésus, CHU de Québec-Université Laval, Québec QC G1J 1Z4, Canada
                [33 ]Departments of Neurology, Pathology, Cell Biology, Systems Biology and Biomedical Informatics, Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA
                [34 ]Cooperative Trials Group for Neuro-Oncology (COGNO) NHMRC Clinical Trials Centre, The University of Sydney, New South Wales, Australia
                [35 ]Departments of Neurosurgery, Public Health Sciences, Henry Ford Health System, Henry Ford Cancer Institute, Detroit, MI 48202, USA
                [36 ]Cure Brain Cancer Biomarkers and Translational Research Group, Prince of Wales Clinical School, UNSW Sydney, Australia
                [37 ]Department of Neurosurgery, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea
                [38 ]Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, 1/F, Prince of Wales Hospital, Shatin, Hong Kong
                [39 ]Department of Oncology, Luxembourg Institute of Health, Luxembourg
                [40 ]Department of Neurosurgery, University of Colorado School of Medicine, Aurora, Colorado, 80045, USA
                [41 ]Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea
                [42 ]Institute of Neuropathology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
                [43 ]Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea
                [44 ]Department of Neurosurgery, University Hospitals-Case Medical Center, Seidman Cancer Center, and the Case Comprehensive Cancer Center, Cleveland, Ohio 44106, USA
                [45 ]The Hospital for Sick Children, Toronto, ON, M5G1X8, Canada
                [46 ]Interdiscplinary Division of Neuro-Oncology, Hertie Institute for Clinical Brain Research, DKTK Partner Site Tübingen, Eberhard Karls University Tübingen, Germany
                [47 ]Department of Neurosurgery, School of Medicine and Winship Cancer Institute of Emory U University; 1365C Clifton Rd. NE, Atlanta, GA30084, USA
                [48 ]Institute of Cancer Genome Sciences, Department of Neurosurgery, University of Birmingham, UK
                [49 ]Department of Neurology, University Hospital Zurich, Zurich, Switzerland
                [50 ]Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
                [51 ]Department of Neurosurgery, Medical University of Vienna, 1090 Vienna, Austria
                [52 ]Institute of Neurology, Medical University of Vienna, 1090 Vienna, Austria
                [53 ]Division of Neurosurgery, Department of Surgery, University Health Network, Toronto, C Canada.
                [54 ]These authors contributed equally.
                Author notes
                [¥ ]Correspondence to roel.verhaak@ 123456jax.org .

                CONTRIBUTIONS

                D.M.A., D.A., P.B., J.S.B., R.B., C.B., P.K.B., D.J.B., A.B., A.C., E.J.C., J.C., G.F., M.N.F., Antonio I., M.D.J., M.K., P.S.L., M.L., P.L., K.L.L., T.M.M., A.M.M., D.N., N.N., H.N., C.Y.N., S.P.N., Houtan N., D.R.O., C.P., L.M.P., G.R., B.R., J.K.S., S.C.S., A.E.S., M.S., L.F.S., H.S., E.G.V.M., C.W., M.W., G.W., A.W., contributed to sample acquisition and processing, sequencing data coordination was performed by H.K, F.P.B and K.C.J., and clinical data coordination by A.D.M., and O.A.. Data analysis was led by F.P.B. and K.C.J. in collaboration with S.B.A., P.B., B.C., J.H.C., H.K., E.K, T.M.M., H.N., J.N., M.S., L.F.S., G.T., F.S.V. and R.G.W.V.. Clinical analysis was performed by A.D.M., L.M.P., and C.W.. Pathology review was completed, in part, by Aruna Chakrabarty, J.T.H., Azzam Ismail., and A.W.. F.P.B., K.C.J., A.D.M., F.S.V., and R.G.W.V. wrote the manuscript. K.D.A. and J.F.D. took charge in coordinating GLASS-MDACC; L.F.S. was the lead coordinator of the GLASS-Leeds cohort and B.A.W. of GLASS-Netherlands. R.G.W.V was the project lead and coordinator. Funding for the project was received by K.D.A., E.B.C., H.G., J.T.H., S.C.S., L.F.S.. All co-authors discussed the results and commented on the manuscript and Supplementary Information.

                Article
                NIHMS1540824
                10.1038/s41586-019-1775-1
                6897368
                31748746
                56b46584-e65b-4e09-a28c-269bded2a4aa

                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Categories
                Article

                Uncategorized
                Uncategorized

                Comments

                Comment on this article