Glioma progression is shaped by genetic evolution and microenvironment interactions

Frederick S. Varn, Kevin C. Johnson, Jan Martinek, Jason T. Huse, MacLean P. Nasrallah, Pieter Wesseling, Lee A.D. Cooper, Tathiane M. Malta, Taylor E. Wade, Thais S. Sabedot, Daniel Brat, Peter V. Gould, Adelheid Wöehrer, Kenneth Aldape, Azzam Ismail, Santhosh K. Sivajothi, Floris P. Barthel, Hoon Kim, Emre Kocakavuk, Nazia AhmedKieron White, Indrani Datta, Hyo Eun Moon, Steven Pollock, Christine Goldfarb, Ga Hyun Lee, Luciano Garofano, Kevin J. Anderson, Djamel Nehar-Belaid, Jill S. Barnholtz-Sloan, Spyridon Bakas, Annette T. Byrne, Fulvio D'Angelo, Hui K. Gan, Mustafa Khasraw, Simona Migliozzi, D. Ryan Ormond, Sun Ha Paek, Erwin G. Van Meir, Annemiek M.E. Walenkamp, Colin Watts, Tobias Weiss, Michael Weller, Karolina Palucka, Lucy F. Stead, Laila M. Poisson, Houtan Noushmehr, Anna Golebiewska, Ann C. Hau, Simone P. Niclou, Roel G.W. Verhaak*, The GLASS Consortium

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

140 Citations (Scopus)


The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions were associated with an increase in proliferating neoplastic cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their neoplastic cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells. Collectively, these recurrence-associated phenotypes represent potential targets to alter disease progression.

Original languageEnglish
Article numbere16
Pages (from-to)2184-2199
Issue number12
Publication statusPublished - 9 Jun 2022


  • genomics
  • glioblastoma
  • glioma
  • hypermutation
  • macrophages
  • microenvironment
  • neurons
  • single-cell
  • spatial imaging
  • treatment resistance


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