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Peer-reviewedCC BYNature

Acquired genetic and cell-state changes in IDH-mutant glioma progression

  • Kevin C. Johnson1
  • Avishay Spitzer2,3
  • Frederick S. Varn4,5,6
  • Masashi Nomura7,8,9,10
  • Luciano Garofano11,12,13
  • Tamrin Chowdhury1
  • Anuja Lipsa14
  • Linbin Zhang1
  • Ester Calvo Fernández7,9,10
  • Tanyeri Barak1
  • A. Gulhan Ercan‐Sencicek1
  • Ayse Buket Peksen1
39 more authors
  • Kevin J. Anderson6
  • C. Mircea S. Tesileanu1
  • Samirkumar B. Amin1
  • Emre Kocakavuk15,1
  • Dacheng Zhao1
  • Fulvio D’Angelo16,12
  • Simona Migliozzi17,12,13
  • Lillian Bussema7,9,10
  • Simon Gritsch7,9,10
  • Hyo-Eun Moon18
  • Sun Ha Paek19,18
  • Franck Bielle20,21
  • Alice Laurenge22,20
  • Anna Luisa Di Stefano23,24
  • Bertrand Mathon25
  • Alberto Pïcca22,21
  • Marc Sanson22,21
  • Ann‐Christin Hau14
  • Frank Hertel14
  • Kamil Grzyb14
  • Zheng Zhao26,27
  • Qianghu Wang28,29
  • Tao Jiang (28401)26,27
  • Julie J. Miller30,31
  • Hiroaki Wakimoto32,31
  • Daniel P. Cahill32,31
  • Jennifer A. Moliterno1
  • Murat Günel1
  • Beth Hermes33
  • Nader Sanai34,33
  • Anna Golebiewska14
  • Simone P. Niclou14
  • Jason T. Huse35
  • W.K. Alfred Yung36
  • Anna Lasorella37,38
  • Mario L. Suvà39,40
  • Antonio Iavarone
  • Itay Tirosh
  • Roel G.W. Verhaak
40 affiliations
  1. 1Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA
  2. 2Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
  3. 3Department of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
  4. 4Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT, USA
  5. 5Institute for Systems Genomics, University of Connecticut, Storrs, CT, USA
  6. 6The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
  7. 7Broad Institute of MIT and Harvard, Cambridge, MA, USA
  8. 8Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  9. 9Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
  10. 10Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
  11. 11Department of Public Health Sciences, Division of Biostatistics, University of Miami, Miller School of Medicine, Miami, FL, USA
  12. 12Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, USA
  13. 13Translational Genomics Research Institute (TGen), Phoenix, AZ, USA
  14. 14NORLUX Neuro-Oncology Laboratory, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
  15. 15Department of Hematology and Stem Cell Transplantation, West German Cancer Center (WTZ), National Center for Tumor Diseases (NCT) West, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
  16. 16Department of Neurological Surgery, University of Miami, Miller School of Medicine, Miami, FL, USA
  17. 17Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, FL, USA
  18. 18Department of Neurosurgery, Cancer Research Institute, Hypoxia Ischemia Disease Institute, Seoul National University, Seoul, Republic of Korea
  19. 19Advanced Institutes of Convergence Technology, Seoul National University, Gyeonggi-do, Republic of Korea
  20. 20AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Neuropathology, Paris, France
  21. 21Sorbonne Université, UMR S 1127, INSERM U 1127, CNRS, ICM-Paris Brain Institute, Equipe Labellisée LNCC, Paris, France
  22. 22AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Neuro-oncology, Paris, France
  23. 23Division of Neurosurgery, Azienda USL Toscana Nord-ovest, Livorno Hospital, Livorno, Italy
  24. 24Neurology Department, Foch Hospital, Suresnes, France
  25. 25AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Neurosurgery, Paris, France
  26. 26Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
  27. 27Chinese Glioma Genome Atlas Network & Asian Glioma Genome Atlas Network, Beijing, China
  28. 28Department of Bioinformatics, Nanjing Medical University, Nanjing, China
  29. 29Institute for Brain Tumors, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
  30. 30Stephen E. and Catherine Pappas Center for Neuro-Oncology, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
  31. 31Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
  32. 32Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
  33. 33St Joseph's Hospital and Barrow Neurological Institute, Phoenix, AZ, USA
  34. 34Ivy Brain Tumor Center at Barrow Neurological Institute, Phoenix, AZ, USA
  35. 35Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  36. 36Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  37. 37Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, FL, USA. [email protected]
  38. 38Department of Public Health Sciences, Division of Biostatistics, University of Miami, Miller School of Medicine, Miami, FL, USA. [email protected]
  39. 39Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected]
  40. 40Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. [email protected]
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Abstract

Gliomas with mutant isocitrate dehydrogenase (IDH) are malignant brain tumours that typically arise in early to mid-adulthood and nearly always recur following treatment 1,2 . However, the genetic and cellular-state changes that drive IDH-mutant glioma progression under treatment remain incompletely understood. Here we integrated single-nucleus transcriptomic profiles, chromatin accessibility profiles and bulk DNA and RNA sequencing from 75 temporally separated gliomas across 35 patients comprising both the oligodendroglioma and astrocytoma IDH-mutant glioma tumour types. We show that malignant cell states transcriptionally resemble stages of normal glial–neuronal lineage development or a reactive mesenchymal-like state, mirroring states previously described in IDH wild-type glioblastoma 3,4 . Malignant cell states displayed distinct chromatin accessibility profiles that were comparable between both IDH-mutant glioma types. The abundance of less differentiated malignant cells increased with grade and with genetic alterations such as PDGFRA amplification. Longitudinal analysis highlighted two major malignant cell-state transition patterns. First, reduced lineage differentiation and increased proliferative malignant cells at recurrence were enriched in gliomas that acquired recurrence-associated genetic events. These included treatment-associated hypermutation, increased copy number changes and cell cycle alterations. Second, increased mesenchymal-like-state abundance occurred independently of acquired genetic alterations and instead coincided with elevated macrophage expression. Overall, our findings provide an integrative model that traces the cell intrinsic and extrinsic factors that shape cellular states during IDH-mutant glioma disease progression.

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Cite

BibTeXRIS
BibTeX
@article{johnson2026acquired,
  title = {{Acquired genetic and cell-state changes in IDH-mutant glioma progression}},
  author = {Kevin C. Johnson and Avishay Spitzer and Frederick S. Varn and Masashi Nomura and Luciano Garofano and Tamrin Chowdhury and Anuja Lipsa and Linbin Zhang and Ester Calvo Fernández and Tanyeri Barak and A. Gulhan Ercan‐Sencicek and Ayse Buket Peksen and Kevin J. Anderson and C. Mircea S. Tesileanu and Samirkumar B. Amin and Emre Kocakavuk and Dacheng Zhao and Fulvio D’Angelo and Simona Migliozzi and Lillian Bussema and Simon Gritsch and Hyo-Eun Moon and Sun Ha Paek and Franck Bielle and Alice Laurenge and Anna Luisa Di Stefano and Bertrand Mathon and Alberto Pïcca and Marc Sanson and Ann‐Christin Hau and Frank Hertel and Kamil Grzyb and Zheng Zhao and Qianghu Wang and Tao Jiang (28401) and Julie J. Miller and Hiroaki Wakimoto and Daniel P. Cahill and Jennifer A. Moliterno and Murat Günel and Beth Hermes and Nader Sanai and Anna Golebiewska and Simone P. Niclou and Jason T. Huse and W.K. Alfred Yung and Anna Lasorella and Mario L. Suvà and Antonio Iavarone and Itay Tirosh and Roel G.W. Verhaak},
  journal = {Nature},
  year = {2026},
  month = jun,
  doi = {10.1038/s41586-026-10612-6},
  url = {https://doi.org/10.1038/s41586-026-10612-6},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Acquired genetic and cell-state changes in IDH-mutant glioma progression
AU  - Kevin C. Johnson
AU  - Avishay Spitzer
AU  - Frederick S. Varn
AU  - Masashi Nomura
AU  - Luciano Garofano
AU  - Tamrin Chowdhury
AU  - Anuja Lipsa
AU  - Linbin Zhang
AU  - Ester Calvo Fernández
AU  - Tanyeri Barak
AU  - A. Gulhan Ercan‐Sencicek
AU  - Ayse Buket Peksen
AU  - Kevin J. Anderson
AU  - C. Mircea S. Tesileanu
AU  - Samirkumar B. Amin
AU  - Emre Kocakavuk
AU  - Dacheng Zhao
AU  - Fulvio D’Angelo
AU  - Simona Migliozzi
AU  - Lillian Bussema
AU  - Simon Gritsch
AU  - Hyo-Eun Moon
AU  - Sun Ha Paek
AU  - Franck Bielle
AU  - Alice Laurenge
AU  - Anna Luisa Di Stefano
AU  - Bertrand Mathon
AU  - Alberto Pïcca
AU  - Marc Sanson
AU  - Ann‐Christin Hau
AU  - Frank Hertel
AU  - Kamil Grzyb
AU  - Zheng Zhao
AU  - Qianghu Wang
AU  - Tao Jiang (28401)
AU  - Julie J. Miller
AU  - Hiroaki Wakimoto
AU  - Daniel P. Cahill
AU  - Jennifer A. Moliterno
AU  - Murat Günel
AU  - Beth Hermes
AU  - Nader Sanai
AU  - Anna Golebiewska
AU  - Simone P. Niclou
AU  - Jason T. Huse
AU  - W.K. Alfred Yung
AU  - Anna Lasorella
AU  - Mario L. Suvà
AU  - Antonio Iavarone
AU  - Itay Tirosh
AU  - Roel G.W. Verhaak
PY  - 2026
DA  - 2026/06/03
JO  - Nature
DO  - 10.1038/s41586-026-10612-6
UR  - https://doi.org/10.1038/s41586-026-10612-6
AB  - Gliomas with mutant isocitrate dehydrogenase (IDH) are malignant brain tumours that typically arise in early to mid-adulthood and nearly always recur following treatment 1,2 . However, the genetic and cellular-state changes that drive IDH-mutant glioma progression under treatment remain incompletely understood. Here we integrated single-nucleus transcriptomic profiles, chromatin accessibility profiles and bulk DNA and RNA sequencing from 75 temporally separated gliomas across 35 patients comprising both the oligodendroglioma and astrocytoma IDH-mutant glioma tumour types. We show that malignant cell states transcriptionally resemble stages of normal glial–neuronal lineage development or a reactive mesenchymal-like state, mirroring states previously described in IDH wild-type glioblastoma 3,4 . Malignant cell states displayed distinct chromatin accessibility profiles that were comparable between both IDH-mutant glioma types. The abundance of less differentiated malignant cells increased with grade and with genetic alterations such as PDGFRA amplification. Longitudinal analysis highlighted two major malignant cell-state transition patterns. First, reduced lineage differentiation and increased proliferative malignant cells at recurrence were enriched in gliomas that acquired recurrence-associated genetic events. These included treatment-associated hypermutation, increased copy number changes and cell cycle alterations. Second, increased mesenchymal-like-state abundance occurred independently of acquired genetic alterations and instead coincided with elevated macrophage expression. Overall, our findings provide an integrative model that traces the cell intrinsic and extrinsic factors that shape cellular states during IDH-mutant glioma disease progression.
SN  - 0028-0836
SN  - 1476-4687
ER  -