Longitudinal molecular trajectories of diffuse glioma in adults.

2019

Barthel, Floris P

Johnson, Kevin C

Varn, Frederick S

Moskalik, Anzhela D

Tanner, Georgette

Kocakavuk, Emre

Anderson, Kevin J

Abiola, Olajide

Aldape, Kenneth

Alfaro, Kristin D

Alpar, Donat

Amin, Samirkumar B

Ashley, David M

Bandopadhayay, Pratiti

Barnholtz-Sloan, Jill S

Beroukhim, Rameen

Bock, Christoph

Brastianos, Priscilla K

Brat, Daniel J

Brodbelt, Andrew R

Bruns, Alexander F

Bulsara, Ketan R

Chakrabarty, Aruna

Chakravarti, Arnab

Chuang, Jeffrey H

Claus, Elizabeth B

Cochran, Elizabeth J

Connelly, Jennifer

Costello, Joseph F

Finocchiaro, Gaetano

Fletcher, Michael N

French, Pim J

Gan, Hui K

Gilbert, Mark R

Gould, Peter V

Grimmer, Matthew R

Iavarone, Antonio

Ismail, Azzam

Jenkinson, Michael D

Khasraw, Mustafa

Kim, Hoon

Kouwenhoven, Mathilde C M

LaViolette, Peter S

Li, Meihong

Lichter, Peter

Ligon, Keith L

Lowman, Allison K

Malta, Tathiane M

Mazor, Tali

McDonald, Kerrie L

Molinaro, Annette M

Nam, Do-Hyun

Nayyar, Naema

Ng, Ho Keung

Ngan, Chew Yee

Niclou, Simone P

Niers, Johanna M

Noushmehr, Houtan

Noorbakhsh, Javad

Ormond, D Ryan

Park, Chul-Kee

Poisson, Laila M

Rabadan, Raul

Radlwimmer, Bernhard

Rao, Ganesh

Reifenberger, Guido

Sa, Jason K

Schuster, Michael

Shaw, Brian L

Short, Susan C

Smitt, Peter A Sillevis

Sloan, Andrew E

Smits, Marion

Suzuki, Hiromichi

Tabatabai, Ghazaleh

Van Meir, Erwin G

Watts, Colin

Weller, Michael

Wesseling, Pieter

Westerman, Bart A

Widhalm, Georg

Woehrer, Adelheid

Yung, W K Alfred

Zadeh, Gelareh

Huse, Jason T

De Groot, John F

Stead, Lucy F

Verhaak, Roel G W

Journal Article

10.1038/s41586-019-1775-1

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.

link

2019; 576(7785): 112-120

Nature