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. BrodbeltAlexander 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. Van 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. De Groot, Lucy F. Stead, Roel G.W. Verhaak, The GLASS Consortium

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)112-120
Number of pages9
JournalNature
Volume576
Issue number7785
DOIs
Publication statusPublished - 5 Dec 2019

Cite this

Barthel, F. P., Johnson, K. C., Varn, F. S., Moskalik, A. D., Tanner, G., Kocakavuk, E., ... The GLASS Consortium (2019). Longitudinal molecular trajectories of diffuse glioma in adults. Nature, 576(7785), 112-120. https://doi.org/10.1038/s41586-019-1775-1