Longitudinal molecular trajectories of diffuse glioma in adults

Research output: Contribution to journalArticlepeer-review


Colleges, School and Institutes

External organisations

  • Department of Pathology, Brain Tumor Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
  • The Jackson Laboratory for Genomic Medicine; Farmington CT 06030 USA
  • Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
  • Department of Neurosurgery, University Hospital Essen, Essen, Germany.
  • Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
  • Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
  • Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, NC, USA.
  • Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
  • Department of Population and Quantitative Health Sciences, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
  • Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
  • Division of Neuro-Oncology, Massachusetts General Hospital, Boston, MA, USA.
  • Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • Department of Neurosurgery, University of Liverpool & Walton Centre NHS Trust, Liverpool, UK.
  • Division of Neurosurgery, The University of Connecticut Health Center, Farmington, CT, USA.
  • Department of Cellular and Molecular Pathology, Leeds Teaching Hospital NHS Trust, St James's University Hospital, Leeds, UK.
  • Department of Radiation Oncology, The Ohio State Comprehensive Cancer Center-Arthur G. James Cancer Hospital, Columbus, OH, USA.
  • Department of Genetics and Genome Sciences, UConn Health, Farmington, CT, USA.
  • Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA.
  • Department of Pathology & Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
  • Department of Neurology, Medical College of Wisconsin, Milwaukee, WI, USA.
  • Department of Neurosurgery, University of California San Francisco, San Francisco, CA, USA.
  • U.O. Neuroradiologia, Fondazione IRCCS Istituto Neurologico Carlo Besta Milano Italy
  • Division of Molecular Genetics, Heidelberg Center for Personalized Oncology, German Cancer Research Consortium, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Department of Neurology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, The Netherlands.
  • La Trobe University School of Cancer Medicine, Heidelberg, Victoria, Australia.
  • Neuro-Oncology Branch, National Institutes of Health, Bethesda, MD, USA.
  • Anatomic Pathology Service, Hôpital de l'Enfant-Jésus, CHU de Québec-Université Laval, Quebec, Quebec, Canada.
  • Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA.
  • Cooperative Trials Group for Neuro-Oncology (COGNO) NHMRC Clinical Trials Centre, The University of Sydney, Sydney, New South Wales, Australia.
  • Department of Neurology, Brain Tumor Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
  • Department of Radiology, Medical College of Wisconsin, Milwaukee, WI, USA.
  • Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Department of Neurosurgery, Henry Ford Health System, Henry Ford Cancer Institute, Detroit, MI, USA.


The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear 1,2. 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.


Original languageEnglish
Pages (from-to)112-120
Number of pages9
Issue number7785
Early online date20 Nov 2019
Publication statusPublished - 5 Dec 2019