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Longitudinal molecular trajectories of diffuse glioma in adults.

Publication ,  Journal Article
Barthel, FP; Johnson, KC; Varn, FS; Moskalik, AD; Tanner, G; Kocakavuk, E; Anderson, KJ; Abiola, O; Aldape, K; Alfaro, KD; Alpar, D; Amin, SB ...
Published in: Nature
December 2019

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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Published In

Nature

DOI

EISSN

1476-4687

Publication Date

December 2019

Volume

576

Issue

7785

Start / End Page

112 / 120

Location

England

Related Subject Headings

  • Recurrence
  • Polymorphism, Single Nucleotide
  • Mutation
  • Isocitrate Dehydrogenase
  • Humans
  • Glioma
  • General Science & Technology
  • Disease Progression
  • Chromosomes, Human, Pair 19
  • Chromosomes, Human, Pair 1
 

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Barthel, F. P., Johnson, K. C., Varn, F. S., Moskalik, A. D., Tanner, G., Kocakavuk, E., … GLASS Consortium, . (2019). Longitudinal molecular trajectories of diffuse glioma in adults. Nature, 576(7785), 112–120. https://doi.org/10.1038/s41586-019-1775-1
Barthel, Floris P., Kevin C. Johnson, Frederick S. Varn, Anzhela D. Moskalik, Georgette Tanner, Emre Kocakavuk, Kevin J. Anderson, et al. “Longitudinal molecular trajectories of diffuse glioma in adults.Nature 576, no. 7785 (December 2019): 112–20. https://doi.org/10.1038/s41586-019-1775-1.
Barthel FP, Johnson KC, Varn FS, Moskalik AD, Tanner G, Kocakavuk E, et al. Longitudinal molecular trajectories of diffuse glioma in adults. Nature. 2019 Dec;576(7785):112–20.
Barthel, Floris P., et al. “Longitudinal molecular trajectories of diffuse glioma in adults.Nature, vol. 576, no. 7785, Dec. 2019, pp. 112–20. Pubmed, doi:10.1038/s41586-019-1775-1.
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. Longitudinal molecular trajectories of diffuse glioma in adults. Nature. 2019 Dec;576(7785):112–120.
Journal cover image

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

December 2019

Volume

576

Issue

7785

Start / End Page

112 / 120

Location

England

Related Subject Headings

  • Recurrence
  • Polymorphism, Single Nucleotide
  • Mutation
  • Isocitrate Dehydrogenase
  • Humans
  • Glioma
  • General Science & Technology
  • Disease Progression
  • Chromosomes, Human, Pair 19
  • Chromosomes, Human, Pair 1