Longitudinal molecular trajectories of diffuse glioma in adults.


Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Barthel, FP; Johnson, KC; Varn, FS; Moskalik, AD; Tanner, G; Kocakavuk, E; Anderson, KJ; Abiola, O; Aldape, K; Alfaro, KD; Alpar, D; Amin, SB; Ashley, DM; Bandopadhayay, P; Barnholtz-Sloan, JS; Beroukhim, R; Bock, C; Brastianos, PK; Brat, DJ; Brodbelt, AR; Bruns, AF; Bulsara, KR; Chakrabarty, A; Chakravarti, A; Chuang, JH; Claus, EB; Cochran, EJ; Connelly, J; Costello, JF; Finocchiaro, G; Fletcher, MN; French, PJ; Gan, HK; Gilbert, MR; Gould, PV; Grimmer, MR; Iavarone, A; Ismail, A; Jenkinson, MD; Khasraw, M; Kim, H; Kouwenhoven, MCM; LaViolette, PS; Li, M; Lichter, P; Ligon, KL; Lowman, AK; Malta, TM; Mazor, T; McDonald, KL; Molinaro, AM; Nam, D-H; Nayyar, N; Ng, HK; Ngan, CY; Niclou, SP; Niers, JM; Noushmehr, H; Noorbakhsh, J; Ormond, DR; Park, C-K; Poisson, LM; Rabadan, R; Radlwimmer, B; Rao, G; Reifenberger, G; Sa, JK; Schuster, M; Shaw, BL; Short, SC; Smitt, PAS; Sloan, AE; Smits, M; Suzuki, H; Tabatabai, G; Van Meir, EG; Watts, C; Weller, M; Wesseling, P; Westerman, BA; Widhalm, G; Woehrer, A; Yung, WKA; Zadeh, G; Huse, JT; De Groot, JF; Stead, LF; Verhaak, RGW; GLASS Consortium,

Published Date

  • December 2019

Published In

Volume / Issue

  • 576 / 7785

Start / End Page

  • 112 - 120

PubMed ID

  • 31748746

Pubmed Central ID

  • 31748746

Electronic International Standard Serial Number (EISSN)

  • 1476-4687

Digital Object Identifier (DOI)

  • 10.1038/s41586-019-1775-1


  • eng

Conference Location

  • England