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Nature. 2019 Dec;576(7785):112-120. doi: 10.1038/s41586-019-1775-1. Epub 2019 Nov 20.

Longitudinal molecular trajectories of diffuse glioma in adults.

Author information

1
The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
2
Department of Pathology, Brain Tumor Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
3
Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
4
DKFZ Division of Translational Neurooncology at the West German Cancer Center, German Cancer Consortium Partner Site, University Hospital Essen, Essen, Germany.
5
Department of Neurosurgery, University Hospital Essen, Essen, Germany.
6
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
7
Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
8
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
9
1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
10
Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, NC, USA.
11
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
12
Broad Institute, Cambridge, MA, USA.
13
Department of Population and Quantitative Health Sciences, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
14
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
15
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
16
Division of Neuro-Oncology, Massachusetts General Hospital, Boston, MA, USA.
17
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
18
Department of Neurosurgery, University of Liverpool & Walton Centre NHS Trust, Liverpool, UK.
19
Division of Neurosurgery, The University of Connecticut Health Center, Farmington, CT, USA.
20
Department of Cellular and Molecular Pathology, Leeds Teaching Hospital NHS Trust, St James's University Hospital, Leeds, UK.
21
Department of Radiation Oncology, The Ohio State Comprehensive Cancer Center-Arthur G. James Cancer Hospital, Columbus, OH, USA.
22
Department of Genetics and Genome Sciences, UConn Health, Farmington, CT, USA.
23
Yale University School of Public Health, New Haven, CT, USA.
24
Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA.
25
Department of Pathology & Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
26
Department of Neurology, Medical College of Wisconsin, Milwaukee, WI, USA.
27
Department of Neurosurgery, University of California San Francisco, San Francisco, CA, USA.
28
Fondazione IRCCS Istituto Neurologico Besta, Milano, Italy.
29
Division of Molecular Genetics, Heidelberg Center for Personalized Oncology, German Cancer Research Consortium, German Cancer Research Center (DKFZ), Heidelberg, Germany.
30
Department of Neurology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, The Netherlands.
31
Olivia Newton-John Cancer Research Institute, Austin Health, Melbourne, Victoria, Australia.
32
La Trobe University School of Cancer Medicine, Heidelberg, Victoria, Australia.
33
Neuro-Oncology Branch, National Institutes of Health, Bethesda, MD, USA.
34
Anatomic Pathology Service, Hôpital de l'Enfant-Jésus, CHU de Québec-Université Laval, Quebec, Quebec, Canada.
35
Department of Neurology, Columbia University Medical Center, New York, NY, USA.
36
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.
37
Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA.
38
Cooperative Trials Group for Neuro-Oncology (COGNO) NHMRC Clinical Trials Centre, The University of Sydney, Sydney, New South Wales, Australia.
39
Department of Neurology, Brain Tumor Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
40
Department of Radiology, Medical College of Wisconsin, Milwaukee, WI, USA.
41
Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
42
Department of Neurosurgery, Henry Ford Health System, Henry Ford Cancer Institute, Detroit, MI, USA.
43
Cure Brain Cancer Biomarkers and Translational Research Group, Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
44
Department of Neurosurgery, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, South Korea.
45
Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, South Korea.
46
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
47
Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
48
Department of Neurosurgery, University of Colorado School of Medicine, Aurora, CO, USA.
49
Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, South Korea.
50
Department of Public Health Sciences, Henry Ford Health System, Henry Ford Cancer Institute, Detroit, MI, USA.
51
Department of Biomedical Informatics, Columbia University Medical Center, New York, NY, USA.
52
Department of Systems Biology, Columbia University, New York, NY, USA.
53
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
54
Institute of Neuropathology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
55
Department of Neurological Surgery, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA.
56
Department of Neurosurgery, Case Western Reserve University, Cleveland, OH, USA.
57
Seidman Cancer Center and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
58
Department of Radiology & Nuclear Medicine, Erasmus MC - University Medical Center Rotterdam, Rotterdam, The Netherlands.
59
The Hospital for Sick Children, Toronto, ON, Canada.
60
Interdiscplinary Division of Neuro-Oncology, Hertie Institute for Clinical Brain Research, DKTK Partner Site Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany.
61
Department of Neurosurgery, School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA, USA.
62
Institute of Cancer Genome Sciences, Department of Neurosurgery, University of Birmingham, Birmingham, UK.
63
Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
64
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
65
Department of Neurosurgery, Brain Tumor Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
66
Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.
67
Institute of Neurology, Medical University of Vienna, Vienna, Austria.
68
Division of Neurosurgery, Department of Surgery, University Health Network, Toronto, Ontario, Canada.
69
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
70
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
71
The 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 unclear1,2. 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.

PMID:
31748746
DOI:
10.1038/s41586-019-1775-1

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