Title

Longitudinal molecular trajectories of diffuse glioma in adults.

Authors

Floris P Barthel, The Jackson LaboratoryFollow
Kevin C Johnson, The Jackson LaboratoryFollow
Frederick S Varn, The Jackson LaboratoryFollow
Anzhela D Moskalik, The Jackson LaboratoryFollow
Georgette Tanner
Emre Kocakavuk, The Jackson LaboratoryFollow
Kevin J Anderson, The Jackson LaboratoryFollow
Olajide Abiola, The Jackson LaboratoryFollow
Kenneth Aldape
Kristin D Alfaro
Donat Alpar
Samirkumar B Amin, The Jackson LaboratoryFollow
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 Chuang, The Jackson LaboratoryFollow
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, The Jackson LaboratoryFollow
Mathilde C M Kouwenhoven
Peter S LaViolette
Meihong Li, The Jackson LaboratoryFollow
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, The Jackson LaboratoryFollow
Simone P Niclou
Johanna M Niers
Houtan Noushmehr
Javad Noorbakhsh, The Jackson LaboratoryFollow
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 Jackson LaboratoryFollow
The GLASS Consortium

Document Type

Article

Publication Date

12-5-2019

Keywords

JGM

JAX Source

Nature 2019 Dec 5; 576:112-120

PMID

31748746

DOI

https://doi.org/10.1038/s41586-019-1775-1

Grant

CA034196,CA16672

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.

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