{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA",
    "Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel",
    "Department of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel",
    "Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT, USA",
    "Institute for Systems Genomics, University of Connecticut, Storrs, CT, USA",
    "The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA",
    "Broad Institute of MIT and Harvard, Cambridge, MA, USA",
    "Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan",
    "Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA",
    "Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA",
    "Department of Public Health Sciences, Division of Biostatistics, University of Miami, Miller School of Medicine, Miami, FL, USA",
    "Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, USA",
    "Translational Genomics Research Institute (TGen), Phoenix, AZ, USA",
    "NORLUX Neuro-Oncology Laboratory, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg",
    "Department 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",
    "Department of Neurological Surgery, University of Miami, Miller School of Medicine, Miami, FL, USA",
    "Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, FL, USA",
    "Department of Neurosurgery, Cancer Research Institute, Hypoxia Ischemia Disease Institute, Seoul National University, Seoul, Republic of Korea",
    "Advanced Institutes of Convergence Technology, Seoul National University, Gyeonggi-do, Republic of Korea",
    "AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Neuropathology, Paris, France",
    "Sorbonne Université, UMR S 1127, INSERM U 1127, CNRS, ICM-Paris Brain Institute, Equipe Labellisée LNCC, Paris, France",
    "AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Neuro-oncology, Paris, France",
    "Division of Neurosurgery, Azienda USL Toscana Nord-ovest, Livorno Hospital, Livorno, Italy",
    "Neurology Department, Foch Hospital, Suresnes, France",
    "AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Neurosurgery, Paris, France",
    "Beijing Neurosurgical Institute, Capital Medical University, Beijing, China",
    "Chinese Glioma Genome Atlas Network & Asian Glioma Genome Atlas Network, Beijing, China",
    "Department of Bioinformatics, Nanjing Medical University, Nanjing, China",
    "Institute for Brain Tumors, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China",
    "Stephen E. and Catherine Pappas Center for Neuro-Oncology, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA",
    "Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA",
    "Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA",
    "St Joseph's Hospital and Barrow Neurological Institute, Phoenix, AZ, USA",
    "Ivy Brain Tumor Center at Barrow Neurological Institute, Phoenix, AZ, USA",
    "Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA",
    "Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA",
    "Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, FL, USA. axl4252@med.miami.edu",
    "Department of Public Health Sciences, Division of Biostatistics, University of Miami, Miller School of Medicine, Miami, FL, USA. axl4252@med.miami.edu",
    "Broad Institute of MIT and Harvard, Cambridge, MA, USA. suva.mario@mgh.harvard.edu",
    "Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. suva.mario@mgh.harvard.edu"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 51,
  "authors": [
    {
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        0
      ],
      "name": "Kevin C. Johnson",
      "orcid": "0000-0003-0016-5158"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Avishay Spitzer",
      "orcid": "0000-0001-6551-9338"
    },
    {
      "affs": [
        3,
        4,
        5
      ],
      "name": "Frederick S. Varn",
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        7,
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      "name": "Masashi Nomura",
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      "name": "Luciano Garofano",
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      "name": "Tamrin Chowdhury",
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      "name": "Anuja Lipsa",
      "orcid": "0000-0002-9668-6048"
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      "name": "Linbin Zhang"
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        9
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      "name": "Ester Calvo Fernández",
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      "name": "Tanyeri Barak",
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      "name": "A. Gulhan Ercan‐Sencicek",
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      "name": "Ayse Buket Peksen"
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      "name": "Kevin J. Anderson",
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      "name": "C. Mircea S. Tesileanu",
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      "name": "Samirkumar B. Amin",
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      "name": "Emre Kocakavuk",
      "orcid": "0000-0003-1920-0494"
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        0
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      "name": "Dacheng Zhao"
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        11
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      "name": "Fulvio D’Angelo",
      "orcid": "0000-0002-4940-4693"
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        11,
        12
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      "name": "Simona Migliozzi",
      "orcid": "0000-0002-4870-8943"
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      "affs": [
        6,
        8,
        9
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      "name": "Lillian Bussema",
      "orcid": "0000-0001-5469-3816"
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    {
      "affs": [
        6,
        8,
        9
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      "name": "Simon Gritsch",
      "orcid": "0000-0001-5682-5712"
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    {
      "affs": [
        17
      ],
      "name": "Hyo-Eun Moon"
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    {
      "affs": [
        18,
        17
      ],
      "name": "Sun Ha Paek",
      "orcid": "0000-0003-3007-8653"
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    {
      "affs": [
        19,
        20
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      "name": "Franck Bielle",
      "orcid": "0000-0001-6564-6388"
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    {
      "affs": [
        21,
        19
      ],
      "name": "Alice Laurenge",
      "orcid": "0000-0002-0058-3176"
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    {
      "affs": [
        22,
        23
      ],
      "name": "Anna Luisa Di Stefano",
      "orcid": "0000-0003-1746-0647"
    },
    {
      "affs": [
        24
      ],
      "name": "Bertrand Mathon",
      "orcid": "0000-0002-9182-5846"
    },
    {
      "affs": [
        21,
        20
      ],
      "name": "Alberto Pïcca",
      "orcid": "0000-0001-7807-5393"
    },
    {
      "affs": [
        21,
        20
      ],
      "name": "Marc Sanson",
      "orcid": "0000-0002-1813-8476"
    },
    {
      "affs": [
        13
      ],
      "name": "Ann‐Christin Hau",
      "orcid": "0000-0002-4412-2355"
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    {
      "affs": [
        13
      ],
      "name": "Frank Hertel",
      "orcid": "0000-0002-2242-4045"
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    {
      "affs": [
        13
      ],
      "name": "Kamil Grzyb",
      "orcid": "0000-0002-2416-9500"
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    {
      "affs": [
        25,
        26
      ],
      "name": "Zheng Zhao",
      "orcid": "0000-0001-8945-9632"
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    {
      "affs": [
        27,
        28
      ],
      "name": "Qianghu Wang",
      "orcid": "0000-0002-3488-1059"
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    {
      "affs": [
        25,
        26
      ],
      "name": "Tao Jiang (28401)"
    },
    {
      "affs": [
        29,
        30
      ],
      "name": "Julie J. Miller",
      "orcid": "0000-0002-1288-593X"
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    {
      "affs": [
        31,
        30
      ],
      "name": "Hiroaki Wakimoto",
      "orcid": "0000-0001-8225-241X"
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    {
      "affs": [
        31,
        30
      ],
      "name": "Daniel P. Cahill",
      "orcid": "0000-0003-2552-6546"
    },
    {
      "affs": [
        0
      ],
      "name": "Jennifer A. Moliterno",
      "orcid": "0000-0002-6413-5874"
    },
    {
      "affs": [
        0
      ],
      "name": "Murat Günel",
      "orcid": "0000-0002-2290-7055"
    },
    {
      "affs": [
        32
      ],
      "name": "Beth Hermes"
    },
    {
      "affs": [
        33,
        32
      ],
      "name": "Nader Sanai",
      "orcid": "0000-0002-5581-0516"
    },
    {
      "affs": [
        13
      ],
      "name": "Anna Golebiewska",
      "orcid": "0000-0002-4160-2521"
    },
    {
      "affs": [
        13
      ],
      "name": "Simone P. Niclou",
      "orcid": "0000-0002-3417-9534"
    },
    {
      "affs": [
        34
      ],
      "name": "Jason T. Huse",
      "orcid": "0000-0003-4514-0640"
    },
    {
      "affs": [
        35
      ],
      "name": "W.K. Alfred Yung",
      "orcid": "0000-0002-1669-0793"
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    {
      "affs": [
        36,
        37
      ],
      "name": "Anna Lasorella",
      "orcid": "0000-0002-1839-5421"
    },
    {
      "affs": [
        38,
        39
      ],
      "name": "Mario L. Suvà",
      "orcid": "0000-0001-9898-5351"
    },
    {
      "name": "Antonio Iavarone",
      "orcid": "0000-0002-0683-4634"
    },
    {
      "name": "Itay Tirosh",
      "orcid": "0000-0001-5477-2987"
    },
    {
      "name": "Roel G.W. Verhaak",
      "orcid": "0000-0003-2773-0436"
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  ],
  "bibtex": "https://research.draconitic.com/paper/3s1q01gmryjpd.bib",
  "cited_by": 14,
  "doi": "10.1038/s41586-026-10612-6",
  "fulltext_url": null,
  "id": "3s1q01gmryjpd",
  "issns": [
    "0028-0836",
    "1476-4687"
  ],
  "landing_url": "https://doi.org/10.1038/s41586-026-10612-6",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2716|Glioma Diagnosis and Treatment"
    ],
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      "2730|Glioma Diagnosis and Treatment"
    ]
  ],
  "openalex": "W7163317224",
  "pdf_url": null,
  "pmcid": "PMC13391360",
  "pmid": "42236943",
  "published": "2026-06-03",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/3s1q01gmryjpd.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:26:56Z",
      "native_id": "W7163317224",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41586-026-10612-6"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2716|Glioma Diagnosis and Treatment",
      "subfield": "human-genetics"
    },
    {
      "field": "medicine",
      "origin": "openalex:2730|Glioma Diagnosis and Treatment",
      "subfield": "oncology"
    }
  ],
  "title": "Acquired genetic and cell-state changes in IDH-mutant glioma progression",
  "title_text": "Acquired genetic and cell-state changes in IDH-mutant glioma progression",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T13:21:16Z",
  "url": "https://research.draconitic.com/paper/3s1q01gmryjpd",
  "venue": "Nature",
  "versions": []
}