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Longitudinal molecular trajectories of diffuse glioma in adults

2019; Nature Portfolio; Volume: 576; Issue: 7785 Linguagem: Inglês

10.1038/s41586-019-1775-1

1476-4687

Floris P Barthel, Kevin C. Johnson, Frederick S. Varn, Anzhela D. Moskalik, Georgette Tanner, Emre Kocakavuk, Kevin Anderson, Olajide Abiola, Kenneth Aldape, Kristin Alfaro-Munoz, Donát Alpár, Samirkumar B. Amin, David M. Ashley, Pratiti Bandopadhayay, Jill S. Barnholtz‐Sloan, Rameen Beroukhim, Christoph Bock, Priscilla K. Brastianos, Daniel J. Brat, Andrew Brodbelt, Alexander Bruns, Ketan R. Bulsara, Aruna Chakrabarty, Arnab Chakravarti, Jeffrey H. Chuang, Elizabeth B. Claus, Elizabeth J. Cochran, Jennifer Connelly, J Costello, Gaetano Finocchiaro, Michael Fletcher, Pim J. French, Hui Gan, Mark R. Gilbert, Peter V. Gould, Matthew Grimmer, Antonio Iavarone, Azzam Ismail, Michael D. Jenkinson, Mustafa Khasraw, Hoon Kim, Mathilde C.M. Kouwenhoven, Peter S. LaViolette, Ho‐Keung Ng, Peter Lichter, Keith L. Ligon, Allison 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 Poisson, Raúl Rabadán, Bernhard Radlwimmer, Hui Gan, Guido Reifenberger, K. Jason, Michael Schuster, Brian Shaw, Susan 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 Wöehrer, W. K. Alfred Yung, Gelareh Zadeh, Jason T. Huse, John de Groot, Lucy F. Stead, Roel G.W. Verhaak, Floris P Barthel, Kevin C. Johnson, Frederick S. Varn, Anzhela D. Moskalik, Georgette Tanner, Emre Kocakavuk, Kevin Anderson, Kenneth Aldape, Kristin Alfaro-Munoz, Samirkumar B. Amin, David M. Ashley, Pratiti Bandopadhayay, Jill S. Barnholtz‐Sloan, Rameen Beroukhim, Christoph Bock, Priscilla K. Brastianos, Daniel J. Brat, Andrew Brodbelt, Ketan R. Bulsara, Aruna Chakrabarty, Jeffrey H. Chuang, Elizabeth B. Claus, Elizabeth J. Cochran, Jennifer Connelly, J Costello, Gaetano Finocchiaro, Michael Fletcher, Pim J. French, Hui Gan, Mark R. Gilbert, Peter V. Gould, Antonio Iavarone, Azzam Ismail, Michael D. Jenkinson, Mustafa Khasraw, Hoon Kim, Mathilde C.M. Kouwenhoven, Peter S. LaViolette, Peter Lichter, Keith L. Ligon, Allison Lowman, Tathiane M. Malta, Kerrie L. McDonald, Annette M. Molinaro, Do‐Hyun Nam, Ho‐Keung Ng, Simone P. Niclou, Johanna M. Niers, Houtan Noushmehr, D. Ryan Ormond, Chul‐Kee Park, Laila Poisson, Raúl Rabadán, Bernhard Radlwimmer, Hui Gan, Guido Reifenberger, K. Jason, Susan Short, Peter A. Sillevis Smitt, Andrew E. Sloan, Marion Smits, Hiromichi Suzuki, Ghazaleh Tabatabai, Erwin G. Van Meir, Colin Watts, Michael Weller, Jelle Wesseling, Bart A. Westerman, Adelheid Wöehrer, W.K. Alfred Yung, Gelareh Zadeh, Jason T. Huse, John de Groot, Lucy F. Stead, Roel G.W. Verhaak,

Single-cell and spatial transcriptomics

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. The GLASS Consortium studies the evolutionary trajectories of 222 patients with a diffuse glioma to aid in our understanding of tumour progression and treatment failure