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    Nature. 2019 Nov 20. doi: 10.1038/s41586-019-1775-1. pii: 10.1038/s41586-019-1775-1
    Longitudinal molecular trajectories of diffuse glioma in adults.
    Barthel FP1,  Johnson KC2,  Varn FS3,  Moskalik AD4,  Tanner G5,  Kocakavuk E6,  Anderson KJ7,  Abiola O8,  Aldape K9,  Alfaro KD10,  Alpar D11,  Amin SB12,  Ashley DM13,  Bandopadhayay P14,  Barnholtz-Sloan JS15,  Beroukhim R16,  Bock C17,  Brastianos PK18,  Brat DJ19,  Brodbelt AR20,  Bruns AF21,  Bulsara KR22,  Chakrabarty A23,  Chakravarti A24,  Chuang JH25,  Claus EB26,  Cochran EJ27,  Connelly J28,  Costello JF29,  Finocchiaro G30,  Fletcher MN31,  French PJ32,  Gan HK33,  Gilbert MR34,  Gould PV35,  Grimmer MR36,  Iavarone A37,  Ismail A38,  Jenkinson MD39,  Khasraw M40,  Kim H41,  Kouwenhoven MCM42,  LaViolette PS43,  Li M44,  Lichter P45,  Ligon KL46,  Lowman AK47,  Malta TM48,  Mazor T49,  McDonald KL50,  Molinaro AM51,  Nam DH52,  Nayyar N53,  Ng HK54,  Ngan CY55,  Niclou SP56,  Niers JM57,  Noushmehr H58,  Noorbakhsh J59,  Ormond DR60,  Park CK61,  Poisson LM62,  Rabadan R63,  Radlwimmer B64,  Rao G65,  Reifenberger G66,  Sa JK67,  Schuster M68,  Shaw BL69,  Short SC70,  Smitt PAS71,  Sloan AE72,  Smits M73,  Suzuki H74,  Tabatabai G75,  Van Meir EG76,  Watts C77,  Weller M78,  Wesseling P79,  Westerman BA80,  Widhalm G81,  Woehrer A82,  Yung WKA83,  Zadeh G84,  Huse JT85,  De Groot JF86,  Stead LF87,  Verhaak RGW88
    Collaborators
    Barthel FP Johnson KC Varn FS Moskalik AD Tanner G Kocakavuk E Anderson KJ Aldape K Alfaro KD Amin SB Ashley DM Bandopadhayay P Barnholtz-Sloan JS Beroukhim R Bock C Brastianos PK Brat DJ Brodbelt AR Bulsara KR Chakrabarty A Chuang JH Claus EB Cochran EJ Connelly J Costello JF Finocchiaro G Fletcher MN French PJ Gan HK Gilbert MR Gould PV Iavarone A Ismail A Jenkinson MD Khasraw M Kim H Kouwenhoven MCM LaViolette PS Lichter P Ligon KL Lowman AK Malta TM McDonald KL Molinaro AM Nam DH Ng HK Niclou SP Niers JM Noushmehr H Ormond DR Park CK Poisson LM Rabadan R Radlwimmer B Rao G Reifenberger G Sa JK Short SC Smitt PAS Sloan AE Smits M Suzuki H Tabatabai G Van Meir EG Watts C Weller M Wesseling P Westerman BA Woehrer A Yung WKA Zadeh G Huse JT De Groot JF Stead LF Verhaak RGW
    Author information
    1The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
    2The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
    3The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
    4The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
    5Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
    6The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
    7The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
    8The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
    9Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
    10Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
    11CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
    12The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
    13Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, NC, USA.
    14Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
    15Department of Population and Quantitative Health Sciences, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
    16Broad Institute, Cambridge, MA, USA.
    17CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
    18Division of Neuro-Oncology, Massachusetts General Hospital, Boston, MA, USA.
    19Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
    20Department of Neurosurgery, University of Liverpool & Walton Centre NHS Trust, Liverpool, UK.
    21Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
    22Division of Neurosurgery, The University of Connecticut Health Center, Farmington, CT, USA.
    23Department of Cellular and Molecular Pathology, Leeds Teaching Hospital NHS Trust, St James's University Hospital, Leeds, UK.
    24Department of Radiation Oncology, The Ohio State Comprehensive Cancer Center-Arthur G. James Cancer Hospital, Columbus, OH, USA.
    25The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
    26Yale University School of Public Health, New Haven, CT, USA.
    27Department of Pathology & Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
    28Department of Neurology, Medical College of Wisconsin, Milwaukee, WI, USA.
    29Department of Neurosurgery, University of California San Francisco, San Francisco, CA, USA.
    30Fondazione IRCCS Istituto Neurologico Besta, Milano, Italy.
    31Division of Molecular Genetics, Heidelberg Center for Personalized Oncology, German Cancer Research Consortium, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    32Department of Neurology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, The Netherlands.
    33Olivia Newton-John Cancer Research Institute, Austin Health, Melbourne, Victoria, Australia.
    34Neuro-Oncology Branch, National Institutes of Health, Bethesda, MD, USA.
    35Anatomic Pathology Service, Hôpital de l'Enfant-Jésus, CHU de Québec-Université Laval, Quebec, Quebec, Canada.
    36Department of Neurosurgery, University of California San Francisco, San Francisco, CA, USA.
    37Department of Neurology, Columbia University Medical Center, New York, NY, USA.
    38Department of Cellular and Molecular Pathology, Leeds Teaching Hospital NHS Trust, St James's University Hospital, Leeds, UK.
    39Department of Neurosurgery, University of Liverpool & Walton Centre NHS Trust, Liverpool, UK.
    40Cooperative Trials Group for Neuro-Oncology (COGNO) NHMRC Clinical Trials Centre, The University of Sydney, Sydney, New South Wales, Australia.
    41The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
    42Department of Neurology, Brain Tumor Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
    43Department of Radiology, Medical College of Wisconsin, Milwaukee, WI, USA.
    44The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
    45Division of Molecular Genetics, Heidelberg Center for Personalized Oncology, German Cancer Research Consortium, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    46Broad Institute, Cambridge, MA, USA.
    47Department of Radiology, Medical College of Wisconsin, Milwaukee, WI, USA.
    48Department of Neurosurgery, Henry Ford Health System, Henry Ford Cancer Institute, Detroit, MI, USA.
    49Department of Neurosurgery, University of California San Francisco, San Francisco, CA, USA.
    50Cure Brain Cancer Biomarkers and Translational Research Group, Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
    51Department of Neurosurgery, University of California San Francisco, San Francisco, CA, USA.
    52Department of Neurosurgery, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, South Korea.
    53Division of Neuro-Oncology, Massachusetts General Hospital, Boston, MA, USA.
    54Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
    55The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
    56Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
    57Department of Neurology, Brain Tumor Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
    58Department of Neurosurgery, Henry Ford Health System, Henry Ford Cancer Institute, Detroit, MI, USA.
    59The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
    60Department of Neurosurgery, University of Colorado School of Medicine, Aurora, CO, USA.
    61Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, South Korea.
    62Department of Public Health Sciences, Henry Ford Health System, Henry Ford Cancer Institute, Detroit, MI, USA.
    63Department of Biomedical Informatics, Columbia University Medical Center, New York, NY, USA.
    64Division of Molecular Genetics, Heidelberg Center for Personalized Oncology, German Cancer Research Consortium, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    65Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
    66Institute of Neuropathology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
    67Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, South Korea.
    68CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
    69Division of Neuro-Oncology, Massachusetts General Hospital, Boston, MA, USA.
    70Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
    71Department of Neurology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, The Netherlands.
    72Department of Neurological Surgery, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA.
    73Department of Radiology & Nuclear Medicine, Erasmus MC - University Medical Center Rotterdam, Rotterdam, The Netherlands.
    74The Hospital for Sick Children, Toronto, ON, Canada.
    75Interdiscplinary Division of Neuro-Oncology, Hertie Institute for Clinical Brain Research, DKTK Partner Site Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany.
    76Department of Neurosurgery, School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA, USA.
    77Institute of Cancer Genome Sciences, Department of Neurosurgery, University of Birmingham, Birmingham, UK.
    78Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
    79Department of Pathology, Brain Tumor Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
    80Department of Neurosurgery, Brain Tumor Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
    81Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.
    82Institute of Neurology, Medical University of Vienna, Vienna, Austria.
    83Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
    84Division of Neurosurgery, Department of Surgery, University Health Network, Toronto, Ontario, Canada.
    85Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
    86Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
    87Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
    88The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA. roel.verhaak@jax.org.
    Abstract

    The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear. Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.


    Publikations ID: 31748746
    Quelle: öffnen
     
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