Primary Mismatch Repair Deficient Glioma (PMMRDG), IDH-wildtype and H3-wildtype: A Giant Cell Tumor with Potential for Long-Term Survival Occurring at all Ages

Abigail K Suwala; Dennis Friedel; Felix E Hinz; Philipp D Mahlknecht; Sophia Schinkewitsch; Mathias Rieder; Nicholas R Fernandez; Lucie Stengs; Yuan Chang; Amit Ringel; Daniel Haag; Stefan Pusch; Damian Stichel; Daniel Schrimpf; Christof M Kramm; Pieter Wesseling; Leonille Schweizer; Patrick Harter; Christian Hartmann; David Capper; Matija Snuderl; Henning Boldt; Sebastian Brandner; Hildegard Dohmen; Till Acker; Jens Schittenhelm; Martin Hasselblatt; Dennis Agardy; Theresa Bunse; Lukas Bunse; Andrey Korshunov; Christel Herold-Mende; Nima Etminan; Wolfgang Wick; Michael Platten; Anirban Das; Uri Tabori; Mirjam Blattner-Johnson; Martin Sill; Dominik Sturm; Stefan M Pfister; David Tw Jones; Felix Sahm; Andreas von Deimling; David E Reuss

doi:10.1093/neuonc/noag132

Primary Mismatch Repair Deficient Glioma (PMMRDG), IDH-wildtype and H3-wildtype: A Giant Cell Tumor with Potential for Long-Term Survival Occurring at all Ages

Neuro Oncol. 2026 Jun 3:noag132. doi: 10.1093/neuonc/noag132. Online ahead of print.

Authors

Abigail K Suwala^{1

2}, Dennis Friedel^{1

2}, Felix E Hinz^{1

2}, Philipp D Mahlknecht^{1

2}, Sophia Schinkewitsch¹, Mathias Rieder¹, Nicholas R Fernandez³, Lucie Stengs³, Yuan Chang³, Amit Ringel³, Daniel Haag^{1

2}, Stefan Pusch^{1

2}, Damian Stichel^{1

2}, Daniel Schrimpf^{1

2}, Christof M Kramm⁴, Pieter Wesseling^{5

6}, Leonille Schweizer^{7

8

9}, Patrick Harter^{9

10

11}, Christian Hartmann¹², David Capper^{13

14}, Matija Snuderl¹⁵, Henning Boldt¹⁶, Sebastian Brandner¹⁷, Hildegard Dohmen¹⁸, Till Acker¹⁸, Jens Schittenhelm¹⁹, Martin Hasselblatt²⁰, Dennis Agardy^{21

22

23}, Theresa Bunse^{21

22

23}, Lukas Bunse^{21

22

23}, Andrey Korshunov^{1

2}, Christel Herold-Mende²⁴, Nima Etminan²⁵, Wolfgang Wick²⁶, Michael Platten^{21

22

23}, Anirban Das^{27

28

29}, Uri Tabori^{27

28

29}, Mirjam Blattner-Johnson^{30

31

32}, Martin Sill^{30

31

32}, Dominik Sturm^{30

31

32}, Stefan M Pfister^{30

31

32}, David Tw Jones^{30

31

32}, Felix Sahm^{1

2}, Andreas von Deimling^{1

2}, David E Reuss^{1

2}

Affiliations

¹ Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg University, Heidelberg, Germany.
² Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
³ Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Ontario, Canada.
⁴ Division of Pediatric Hematology and Oncology, University Medical Center Goettingen, Goettingen, Germany.
⁵ Department of Pathology, Amsterdam University Medical Centers, Location VUmc and Brain Tumor Center Amsterdam, Amsterdam, The Netherlands.
⁶ Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
⁷ Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany.
⁸ German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁹ Institute of Neurology (Edinger Institute), University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany.
¹⁰ Bavarian Cancer Research Center (BZKF), Erlangen, 91054, Germany.
¹¹ Center for Neuropathology and Prion Research, Faculty of Medicine LMU Munich, Ludwig-Maximilians-University (LMU), Munich, Germany.
¹² German Cancer Consortium (DKTK), Partner Site Munich, A Partnership Between the DKFZ Heidelberg and the University Hospital of the LMU, Munich, Germany.
¹³ Department of Neuropathology, Institute of Pathology, Hannover Medical School (MHH), Hannover, Germany.
¹⁴ Department of Neuropathology, Charité -, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany.
¹⁵ Partner Site Berlin, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
¹⁶ Department of Pathology, NYU Grossman School of Medicine, New York, New York, USA.
¹⁷ Department of Pathology, Odense University Hospital, University of Southern Denmark, Odense, Denmark.
¹⁸ Division of Neuropathology, The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK.
¹⁹ Institute of Neuropathology, Justus-Liebig University Giessen, Giessen, Germany.
²⁰ Department of Neuropathology, Institute of Pathology and Neuropathology, Tübingen, Germany.
²¹ Institute of Neuropathology, University Hospital Münster, Münster, Germany.
²² German Cancer Research Center (DKFZ), Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, Heidelberg, Germany.
²³ German Cancer Consortium (DKTK), DKFZ Core Center, Heidelberg, Germany.
²⁴ Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translation Neuroscience (MCTN), Heidelberg University, Mannheim, Germany.
²⁵ Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany.
²⁶ Department of Neurosurgery, University Hospital Mannheim, Mannheim, Germany.
²⁷ Neurology Clinic, National Center for Tumor Diseases & European Center for Neurooncology (EZN), University Hospital Heidelberg, Heidelberg University, Heidelberg, Germany.
²⁸ Neuro-Oncology Unit, Division of Haematology Oncology, The Hospital for Sick Children, Toronto, Canada.
²⁹ Department of Paediatrics and Institute of Medical Sciences, University of Toronto, Toronto, Canada.
³⁰ Brain Tumor Research Center and Genetics and Genome Biology Program, SickKids Research Institute, Toronto, Canada.
³¹ Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
³² Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germanyand.

PMID: 42236272
DOI: 10.1093/neuonc/noag132

Abstract

Background: Replication-repair-deficiency is associated with increased risk of developing malignant gliomas. The aim of this study was to investigate primary mismatch repair deficient gliomas (PMMRDGs), a group of IDH-wildtype and H3-wildtype gliomas that is enriched among patients with CMMRD and Lynch syndrome.

Methods: We investigated how PMMRDGs differ from other gliomas with respect to DNA methylation profile, genomic alterations, histopathology, and clinical outcomes.

Results: PMMRDGs occur in pediatric, adolescents and the elderly, falling in two related methylation clusters and are characterized by a high frequency of replication repair deficiency. Histology showed multinucleated giant cells, and immunohistochemistry demonstrated loss of MMR protein expression. Survival analysis revealed long-term survival in patients with high mutational burden (>50 mut/Mb) and an intact chromosome 9p region, which was validated in an independent reference cohort.

Conclusions: Overall, our findings indicate that PMMRDGs represent a distinct type of IDH-wildtype gliomas with potential for long-term survival likely driven by immune activation.

Keywords: MMRD; Mismatch repair; long-term survivor; lynch; type I interferon.

Plain language summary

In this study we investigate a group of brain tumors linked to inherited problems in DNA repair. These tumors can occur in children, adolescents, and older adults. We analyzed their molecular features, tissue appearance, and patient outcomes and found that these tumors form a distinct group with many genetic changes and characteristic giant tumor cells. Importantly, some patients lived much longer, especially when their tumors had a very high number of mutations and retained a specific chromosome region. These findings show that this tumor type is biologically unique and may benefit from immune system activity, offering hope for improved treatment strategies.

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