Longitudinal molecular trajectories of diffuse glioma in adults

Floris P. Barthel, Kevin C. Johnson, Frederick S. Varn, Anzhela D. Moskalik, Georgette Tanner, Emre Kocakavuk, Kevin J. Anderson, Olajide Abiola, Kenneth Aldape, Kristin D. Alfaro, Donat Alpar, Samirkumar B. Amin, David M. Ashley, Pratiti Bandopadhayay, Jill S. Barnholtz-Sloan, Rameen Beroukhim, Christoph Bock, Priscilla K. Brastianos, Daniel J. Brat, Andrew R. Brodbelt, Alexander F. Bruns, Ketan R. Bulsara, Aruna Chakrabarty, Arnab Chakravarti, Jeffrey H. Chuang, Elizabeth B. Claus, Elizabeth J. Cochran, Jennifer Connelly, Joseph F. Costello, Gaetano Finocchiaro, Michael N. Fletcher, Pim J. French, Hui K. Gan, Mark R. Gilbert, Peter V. Gould, Matthew R. Grimmer, Antonio Iavarone, Azzam Ismail, Michael D. Jenkinson, Mustafa Khasraw, Hoon Kim, Mathilde C. M. Kouwenhoven, Peter S. LaViolette, Meihong Li, Peter Lichter, Keith L. Ligon, Allison K. Lowman, Tathiane M. Malta, Tali Mazor, Kerrie L. McDonald, Annette M. Molinaro, Do-Hyun Nam, Naema Nayyar, Ho Keung Ng, Chew Yee Ngan, Simone P. Niclou, Johanna M. Niers, Houtan Noushmehr, Javad Noorbakhsh, D. Ryan Ormond, Chul-Kee Park, Laila M. Poisson, Raul Rabadan, Bernhard Radlwimmer, Ganesh Rao, Guido Reifenberger, Jason K. Sa, Michael Schuster, Brian L. Shaw, Susan C. Short, Peter A. Sillevis Smitt, Andrew E. Sloan, Marion Smits, Hiromichi Suzuki, Ghazaleh Tabatabai, Erwin G. Meir, Colin Watts, Michael Weller, Pieter Wesseling, Bart A. Westerman, Georg Widhalm, Adelheid Woehrer, W. K. Alfred Yung, Gelareh Zadeh, Jason T. Huse, John F. Groot, Lucy F. Stead and Roel G. W. Verhaak ()
Additional contact information
Floris P. Barthel: The Jackson Laboratory for Genomic Medicine
Kevin C. Johnson: The Jackson Laboratory for Genomic Medicine
Frederick S. Varn: The Jackson Laboratory for Genomic Medicine
Anzhela D. Moskalik: The Jackson Laboratory for Genomic Medicine
Georgette Tanner: University of Leeds
Emre Kocakavuk: The Jackson Laboratory for Genomic Medicine
Kevin J. Anderson: The Jackson Laboratory for Genomic Medicine
Olajide Abiola: The Jackson Laboratory for Genomic Medicine
Kenneth Aldape: National Cancer Institute
Kristin D. Alfaro: The University of Texas MD Anderson Cancer Center
Donat Alpar: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Samirkumar B. Amin: The Jackson Laboratory for Genomic Medicine
David M. Ashley: Duke University Medical Center
Pratiti Bandopadhayay: Dana-Farber Cancer Institute
Jill S. Barnholtz-Sloan: Case Western Reserve University School of Medicine
Rameen Beroukhim: Broad Institute
Christoph Bock: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Priscilla K. Brastianos: Massachusetts General Hospital
Daniel J. Brat: Northwestern University Feinberg School of Medicine
Andrew R. Brodbelt: University of Liverpool & Walton Centre NHS Trust
Alexander F. Bruns: University of Leeds
Ketan R. Bulsara: The University of Connecticut Health Center
Aruna Chakrabarty: St James’s University Hospital
Arnab Chakravarti: The Ohio State Comprehensive Cancer Center–Arthur G. James Cancer Hospital
Jeffrey H. Chuang: The Jackson Laboratory for Genomic Medicine
Elizabeth B. Claus: Yale University School of Public Health
Elizabeth J. Cochran: Medical College of Wisconsin
Jennifer Connelly: Medical College of Wisconsin
Joseph F. Costello: University of California San Francisco
Gaetano Finocchiaro: Fondazione IRCCS Istituto Neurologico Besta
Michael N. Fletcher: German Cancer Research Center (DKFZ)
Pim J. French: Erasmus MC – University Medical Center Rotterdam
Hui K. Gan: Austin Health, Melbourne
Mark R. Gilbert: National Institutes of Health
Peter V. Gould: Hôpital de l’Enfant-Jésus, CHU de Québec-Université Laval
Matthew R. Grimmer: University of California San Francisco
Antonio Iavarone: Columbia University Medical Center
Azzam Ismail: St James’s University Hospital
Michael D. Jenkinson: University of Liverpool & Walton Centre NHS Trust
Mustafa Khasraw: The University of Sydney
Hoon Kim: The Jackson Laboratory for Genomic Medicine
Mathilde C. M. Kouwenhoven: Vrije Universiteit Amsterdam
Peter S. LaViolette: Medical College of Wisconsin
Meihong Li: The Jackson Laboratory for Genomic Medicine
Peter Lichter: German Cancer Research Center (DKFZ)
Keith L. Ligon: Broad Institute
Allison K. Lowman: Medical College of Wisconsin
Tathiane M. Malta: Henry Ford Cancer Institute
Tali Mazor: University of California San Francisco
Kerrie L. McDonald: University of New South Wales
Annette M. Molinaro: University of California San Francisco
Do-Hyun Nam: Sungkyunkwan University School of Medicine, Samsung Medical Center
Naema Nayyar: Massachusetts General Hospital
Ho Keung Ng: The Chinese University of Hong Kong, Prince of Wales Hospital
Chew Yee Ngan: The Jackson Laboratory for Genomic Medicine
Simone P. Niclou: Luxembourg Institute of Health
Johanna M. Niers: Vrije Universiteit Amsterdam
Houtan Noushmehr: Henry Ford Cancer Institute
Javad Noorbakhsh: The Jackson Laboratory for Genomic Medicine
D. Ryan Ormond: University of Colorado School of Medicine
Chul-Kee Park: Seoul National University College of Medicine, Seoul National University Hospital
Laila M. Poisson: Henry Ford Cancer Institute
Raul Rabadan: Columbia University Medical Center
Bernhard Radlwimmer: German Cancer Research Center (DKFZ)
Ganesh Rao: The University of Texas MD Anderson Cancer Center
Guido Reifenberger: Heinrich Heine University Düsseldorf
Jason K. Sa: Samsung Medical Center
Michael Schuster: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Brian L. Shaw: Massachusetts General Hospital
Susan C. Short: University of Leeds
Peter A. Sillevis Smitt: Erasmus MC – University Medical Center Rotterdam
Andrew E. Sloan: Case Western Reserve University
Marion Smits: Erasmus MC – University Medical Center Rotterdam
Hiromichi Suzuki: The Hospital for Sick Children
Ghazaleh Tabatabai: DKTK Partner Site Tübingen, Eberhard Karls University Tübingen
Erwin G. Meir: School of Medicine and Winship Cancer Institute of Emory University
Colin Watts: University of Birmingham
Michael Weller: University Hospital Zurich
Pieter Wesseling: Amsterdam UMC, Vrije Universiteit Amsterdam
Bart A. Westerman: Amsterdam UMC, Vrije Universiteit Amsterdam
Georg Widhalm: Medical University of Vienna
Adelheid Woehrer: Medical University of Vienna
W. K. Alfred Yung: The University of Texas MD Anderson Cancer Center
Gelareh Zadeh: University Health Network
Jason T. Huse: The University of Texas MD Anderson Cancer Center
John F. Groot: The University of Texas MD Anderson Cancer Center
Lucy F. Stead: University of Leeds
Roel G. W. Verhaak: The Jackson Laboratory for Genomic Medicine

Nature, 2019, vol. 576, issue 7785, 112-120

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1775-1

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