. 2025 Jul 30;27(6):1519-1535.

doi: 10.1093/neuonc/noaf015.

The clinical and molecular landscape of diffuse hemispheric glioma, H3 G34-mutant

Emilie Le Rhun^{1

2

3}, Andrea Bink⁴, Joerg Felsberg^{5

6}, Dorothee Gramatzki², Sebastian Brandner^{7

8}, Jamal K Benhamida⁹, Antje Wick^{10

11}, Joerg C Tonn^{12

13}, Malte Mohme¹⁴, Ghazaleh Tabatabai^{15

16

17

18}, David Capper^{19

20}, Matija Snuderl²¹, Evangelia Razis²², Michael W Ronellenfitsch^{23

24}, Nicolas Neidert²⁵, Ho-Keung Ng²⁶, Ute Pohl²⁷, Tejus Bale⁹, Stefanie Quach^{28

12

13}, David Rieger¹⁸, Ulrich Schüller^{29

30

31}, Julia Onken^{32

33

19}, Katharina Drüschler^{10

11}, Claude-Alain Maurage³⁴, Luca Regli³, Estelle Healy³⁵, Maya Graham³⁶, Tibor Hortobagyi³⁷, Simon Paine³⁸, Leslie Bridges³⁹, Tereza Lausova^{40

41}, Valentina Medici⁴, Philipp Sievers^{40

41}, David Schrimpf^{40

41}, Wolfgang Wick^{10

11}, Felix Sahm^{40

41}, Guido Reifenberger^{5

6}, Andreas von Deimling^{40

41}, Michael Weller²

Affiliations

¹ Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland.
² Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.
³ Department of Neurosurgery, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland.
⁴ Department of Neuroradiology, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland.
⁵ German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Düsseldorf, Germany.
⁶ Institute of Neuropathology, Medical Faculty, Heinrich Heine University and University Hospital Düsseldorf, Düsseldorf, Germany.
⁷ Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London, UK.
⁸ Division of Neuropathology, National Hospital for Neurology and Neurosurgery, University College London NHS Foundation Trust, London, UK.
⁹ Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
¹⁰ Department of Neurology and Neurooncology Program, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
¹¹ Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹² German Consortium for Translational Cancer Research (DKTK), PartnerSite Munich, Munich, Germany.
¹³ Department of Neurosurgery, University Hospital, LMU Munich, Munich, Germany.
¹⁴ Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁵ Center for Neuro-Oncology, Comprehensive Cancer Center Tübingen-Stuttgart, Eberhard Karls University Tübingen, Tübingen, Germany.
¹⁶ German Consortium for Translational Cancer Research (DKTK), Partner Site Tübingen, Tübingen, Germany.
¹⁷ Cluster of Excellence (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies," Eberhard Karls University Tübingen, Tübingen, Germany.
¹⁸ Department of Neurology & Interdisciplinary Neuro-Oncology, University Hospital Tübingen, Hertie Institute for Clinical Brain Research, Eberhard Karls University Tübingen, Tübingen, Germany.
¹⁹ German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁰ Department of Neuropathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
²¹ Department of Pathology, Molecular Pathology and Diagnostics, NYU Langone Medical Center, New York, New York, USA.
²² Department of Oncology, Hygeia Hospital, Athens, Greece.
²³ University Cancer Center (UCT), University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany.
²⁴ Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany.
²⁵ Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.
²⁶ Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong, Hong Kong.
²⁷ Department of Histopathology, Department of Cellular Pathology, University Hospital Birmingham, Birmingham, UK.
²⁸ Department of Neurosurgery (Evangelisches Klinikum Bethel), Medical School, Bielefeld University, Bielefeld, Germany.
²⁹ Research Institute Children's Cancer Center Hamburg, Hamburg, Germany.
³⁰ Department of Pediatric Hematology and Oncology, Research Institute Children's Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
³¹ Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
³² Humboldt-University, Berlin, Germany.
³³ Department of Neurosurgery, Charité University Medicine Berlin, Berlin, Germany.
³⁴ Department of Pathology, Centre Biologie Pathologie, Lille University Hospital, Hopital Nord, Lille, France.
³⁵ Department of Pathology, Royal Hospitals, Belfast, Northern Ireland.
³⁶ Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
³⁷ Department of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
³⁸ Department of Cellular Pathology, Queen's Medical Centre Campus, Nottingham, UK.
³⁹ Department of Cellular Pathology, St George's University Hospitals NHS Foundation Trust St George's Hospital, London, UK.
⁴⁰ Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴¹ Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.

PMID: 39842935
PMCID: PMC12309718
DOI: 10.1093/neuonc/noaf015

The clinical and molecular landscape of diffuse hemispheric glioma, H3 G34-mutant

Emilie Le Rhun et al. Neuro Oncol. 2025.

. 2025 Jul 30;27(6):1519-1535.

doi: 10.1093/neuonc/noaf015.

Authors

Affiliations

¹ Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland.
² Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.
³ Department of Neurosurgery, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland.
⁴ Department of Neuroradiology, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland.
⁵ German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Düsseldorf, Germany.
⁶ Institute of Neuropathology, Medical Faculty, Heinrich Heine University and University Hospital Düsseldorf, Düsseldorf, Germany.
⁷ Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London, UK.
⁸ Division of Neuropathology, National Hospital for Neurology and Neurosurgery, University College London NHS Foundation Trust, London, UK.
⁹ Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
¹⁰ Department of Neurology and Neurooncology Program, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
¹¹ Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹² German Consortium for Translational Cancer Research (DKTK), PartnerSite Munich, Munich, Germany.
¹³ Department of Neurosurgery, University Hospital, LMU Munich, Munich, Germany.
¹⁴ Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁵ Center for Neuro-Oncology, Comprehensive Cancer Center Tübingen-Stuttgart, Eberhard Karls University Tübingen, Tübingen, Germany.
¹⁶ German Consortium for Translational Cancer Research (DKTK), Partner Site Tübingen, Tübingen, Germany.
¹⁷ Cluster of Excellence (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies," Eberhard Karls University Tübingen, Tübingen, Germany.
¹⁸ Department of Neurology & Interdisciplinary Neuro-Oncology, University Hospital Tübingen, Hertie Institute for Clinical Brain Research, Eberhard Karls University Tübingen, Tübingen, Germany.
¹⁹ German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁰ Department of Neuropathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
²¹ Department of Pathology, Molecular Pathology and Diagnostics, NYU Langone Medical Center, New York, New York, USA.
²² Department of Oncology, Hygeia Hospital, Athens, Greece.
²³ University Cancer Center (UCT), University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany.
²⁴ Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany.
²⁵ Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.
²⁶ Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong, Hong Kong.
²⁷ Department of Histopathology, Department of Cellular Pathology, University Hospital Birmingham, Birmingham, UK.
²⁸ Department of Neurosurgery (Evangelisches Klinikum Bethel), Medical School, Bielefeld University, Bielefeld, Germany.
²⁹ Research Institute Children's Cancer Center Hamburg, Hamburg, Germany.
³⁰ Department of Pediatric Hematology and Oncology, Research Institute Children's Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
³¹ Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
³² Humboldt-University, Berlin, Germany.
³³ Department of Neurosurgery, Charité University Medicine Berlin, Berlin, Germany.
³⁴ Department of Pathology, Centre Biologie Pathologie, Lille University Hospital, Hopital Nord, Lille, France.
³⁵ Department of Pathology, Royal Hospitals, Belfast, Northern Ireland.
³⁶ Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
³⁷ Department of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
³⁸ Department of Cellular Pathology, Queen's Medical Centre Campus, Nottingham, UK.
³⁹ Department of Cellular Pathology, St George's University Hospitals NHS Foundation Trust St George's Hospital, London, UK.
⁴⁰ Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴¹ Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.

PMID: 39842935
PMCID: PMC12309718
DOI: 10.1093/neuonc/noaf015

Abstract

Background: Diffuse hemispheric glioma, histone 3 (H3) G34-mutant, has been newly defined in the 2021 World Health Organization (WHO) classification of central nervous system tumors. Here we sought to define the prognostic roles of clinical, neuroimaging, pathological, and molecular features of these tumors.

Methods: We retrospectively assembled a cohort of 114 patients (median age 22 years) with diffuse hemispheric glioma, H3 G34-mutant, central nervous system WHO grade 4, and profiled the imaging, histological, and molecular landscape of their tumors.

Results: Compared with glioblastoma, H3 G34-mutant diffuse hemispheric gliomas exhibited less avid contrast enhancement, necrosis, and edema on MRI. Comprehensive analyses of mutational and DNA copy number profiles revealed recurrent mutations in TP53 and ATRX, homozygous deletions of CDKN2A/B, and amplifications of PDGFRA, EGFR, CCND2, and MYCN. MGMT promoter methylation was detected in 79 tumors (75%); 11 tumors (13%) showed DNA copy number profiles suggestive of circumscribed deletions on 10q26.3 involving the MGMT locus. Median survival was 21.5 months. Female sex, gross total resection, and MGMT promoter methylation were positive prognostic factors on univariate analysis. Among radiological, pathological, and molecular features, the absence of pial invasion and the presence of microvascular proliferation and CDK6 amplification were positive prognostic factors on univariate analyses.

Conclusions: This study refines the clinical and molecular landscape of H3 G34-mutant diffuse hemispheric gliomas. Dedicated trials for this novel tumor type are urgently needed.

Keywords: MGMT; glioblastoma; histone; loss; methylation.

PubMed Disclaimer

Conflict of interest statement

E.L.R. has received research grants from Bristol Meyers Squibb (BMS), and honoraria for lectures or advisory board participation or consulting from Astra Zeneca Daiichi, Bayer, Biodexa/Sitoxi, Janssen, Leo Pharma, Pfizer, Pierre Fabre, Roche, Seattle Genetics, and Servier.

A.B. declares no conflicts of interest.

J.F. declares no conflicts of interest.

D.G. declares no conflicts of interest.

S.B. has received honoraria for lectures or advisory board participation from Bayer and B. Braun.

J.K.B. declares no conflicts of interest.

A.W. declares no conflicts of interest.

J.C.T. has received honoraria for consulting AAA-Novartis and for traveling costs from Servier.

M.M. declares no conflict of interest.

G.T. has served on advisory boards (Bayer, Boehringer Ingelheim, CureVac, Miltenyi Biomedicine, Novocure), as a consultant (Bayer, Boehringer Ingelheim, CureVac), as steering committee member in noninterventional trials (Bayer, Novocure), as a speaker (Novocure, Servier), and financial compensation for all these activities was provided as institutional funding to the University Hospital Tübingen.

D.C. has received research grants from Novocure and is a cofunder and shareholder of Heidelberg Epignostix GmbH.

M.S. is a scientific Advisor, and Shareholder for HAloDx, Heidelberg Epignostix, and a scientific advisor for InnoSIGN and Arima Genomics.

E.R. has received honoraria and conference attendance support by Astra Zeneca, Servier, Gilead, Pfizer, Novartis, and Glaxo.

M.W.R. reports a research grant from UCB as well as an honoraria for advisory board participation from Alexion.

N.N. declares no conflict of interest.

H.-K.N. declares no conflicts of interest.

U.P. declares no conflict of interest.

T.B. declares no conflicts of interest.

S.Q. declares no conflicts of interest.

D.R. declares no conflicts of interest.

U.S. declares no conflicts of interest.

J.O. received research grants from Novocure and Olympus.

K.D. declares no conflicts of interest.

C.-A.M. declares no conflicts of interest.

L.R. declares no conflicts of interest.

E.H. declares no conflicts of interest.

M.G. declares no conflicts of interest.

T.H. declares no conflicts of interest.

S.P. declares no conflicts of interest.

L.B. declares no conflicts of interest.

T.L. declares no conflicts of interest.

V.M. declares no conflicts of interest.

P.S. declares no conflicts of interest.

D.S. declares no conflicts of interest.

W.W. declares no conflicts of interest.

F.S. is a cofounder and shareholder of Heidelberg Epignostix GmbH.

G.R. declares no conflicts of interest.

A.v.D. declares no conflicts of interest.

M.W. has received research grants from Novartis, Quercis, and Versameb, and honoraria for lectures or advisory board participation or consulting from Bayer, CureVac, Medac, Novartis, Novocure, Orbus, Philogen, Roche, Sandoz and Servier.

Figures

**Figure 1.**
**Typical MRI features of G34-mutant glioma.** (A) Axial sequences (1, 5, 9: T1-weighted sequences without contrast, 2,6,10: contrast-enhanced T1-weighted sequences, 3, 7, 11: FLAIR sequences; 4, 8,12: T2-weighted sequences). 1-4: 8-year-old patient with an intra-axial frontal H3 G34V-mutant diffuse hemispheric glioma with involvement of the cortex and white matter, calvarial remodeling, mild contrast enhancement, minimal necrosis, and relatively small edema. 5-8: 28-year-old patient with an H3 G34R-mutant extensive intra-axial diffuse hemispheric glioma extending via the forceps major into both hemispheres with edema, small areas of necrosis, and minimal contrast enhancement. 9-12: 60-year-old patient with an intra-axial left-sided fronto-insular tumor with peripheral marked enhancement, extensive necrosis, and edema, histologically diagnosed as glioblastoma, IDH-wildtype. (B) Neuroimaging features of G34-mutant diffuse hemispheric glioma: comparison with glioblastoma, IDH-wildtype. IDH, isocitrate dehydrogenase.

**Figure 2.**
**Molecular characterization of diffuse hemispheric glioma, H3 G34-mutant. (**A) tSNE plot in distinction to other types of gliomas in adulthood from the GGN cohort, including IDH-wildtype glioblastoma subclass mesenchymal (N = 20), subclass RTK1 (N = 20), subclass RTK2 (N = 20), and IDH-mutant glioma, subclass high-grade astrocytoma (N = 20), subclass astrocytoma (N = 20), and subclass 1p/19q-codeleted oligodendroglioma (N = 20) (blue arrows: tumors with typical H3 G34 methylation profile but without H3 G34 mutation identified by local analysis or central gene panel sequencing; green arrow: the single H3 G34-mutant tumor with an IDH mutation confirmed by local analysis and central gene panel sequencing. DNA methylation profiling was done on 65 newly diagnosed tumors, 6 recurrent tumors, and 13 patients where this information was lacking, for overall 84 patients (74%). (B) CNV profiles in distinction to the other types of gliomas as in A. GGH, German Glioma Network; IDH, isocitrate dehydrogenase; RTK, receptor tyrosine kinase.

**Figure 3.**
**Mutational landscape of diffuse hemispheric gliomas, H3 G34-mutant. (**A) Mutational landscape of diffuse hemispheric glioma, H3 G34-mutant. The tumor mutational burden (TMB) part shows the total number of mutations per megabase. (B) CoBarplot of H3 G34-mutant gliomas (left) compared with glioblastoma, IDH-wildtype (right). IDH, IDH, isocitrate dehydrogenase.

**Figure 4.**
**Survival analyses in patients with diffuse hemispheric glioma, H3 G34-mutant.** Progression-free (A) and overall survival (B) are depicted by Kaplan-Meier curves. (C) Overall survival with diffuse hemispheric glioma, G34-mutant, split by age. A-C include data on the reference cohort of patients with glioblastoma, IDH-wildtype, E-H contain data on H3 G34-mutant diffuse hemispheric glioma. Survival associations with sex (D) and extent of resection (E). Survival associations by *MGMT* promoter methylation (F) and by focal underrepresentation of chromosome 10 including the *MGMT* locus (cutoff: −0.5) (G) stratified by *MGMT* promoter methylation status (H). The log-rank test was used for comparison, and a P value of.05 was defined as statistically significant. IDH, isocitrate dehydrogenase; MGMT, O⁶-methylguanine DNA methyltransferase.

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References

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The clinical and molecular landscape of diffuse hemispheric glioma, H3 G34-mutant

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The clinical and molecular landscape of diffuse hemispheric glioma, H3 G34-mutant

Authors

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Conflict of interest statement

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