Longitudinal molecular trajectories of diffuse glioma in adults

胶质瘤 生物 体细胞突变 癌症研究 基因 表型 癌症的体细胞进化 非整倍体 细胞周期 遗传学 染色体 抗体 B细胞
作者
Floris P Barthel,Kevin C. Johnson,Frederick S. Varn,Anzhela D. Moskalik,Georgette Tanner,Emre Kocakavuk,Kevin J. Anderson,Olajide Abiola,Kenneth Aldape,Kristin Alfaro-Munoz,Donát Alpár,Samirkumar B. Amin,David Ashley,Pratiti Bandopadhayay,Jill S. Barnholtz‐Sloan,Rameen Beroukhim,Christoph Bock,Priscilla 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,Joseph F. Costello,Gaetano Finocchiaro,Michael Fletcher,Pim J. French,Hui 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 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,Ganesh Rao,Guido Reifenberger,K. Jason,Michael Schuster,Brian Shaw,Susan C Short,Peter A.E. 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 F. de Groot,Lucy F. Stead,Roel G.W. Verhaak
出处
期刊:Nature [Nature Portfolio]
卷期号:576 (7785): 112-120 被引量:335
标识
DOI:10.1038/s41586-019-1775-1
摘要

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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