High peritumoral network connectedness in glioblastoma reveals a distinct epigenetic signature and is associated with decreased overall survival

Neuro-Oncology, vol. 27, pp. 2564–2573

Abstract

BACKGROUND: Glioblastomas are functionally integrated into their peritumoral neural environment, and the dynamic functional interaction can be analyzed using network theory, providing insights into the tumor-brain interface. We investigated the peritumoral network connectedness of glioblastomas, revealing its association with distinct epigenetic signatures, its influence on survival, and its susceptibility to modification through surgical treatment. METHODS: Resting-state fMRI was performed on 48 glioblastoma patients. Tumor lesions were segmented, and networks were constructed at 10 mm and 40 mm distances from the tumor margin. These networks were mirrored to the healthy hemisphere to compare lesional and contralesional networks. The difference between lesional and contralesional mean degree centrality was calculated to assess the peritumoral network connectedness. Its correlation with epigenetic signatures and effect on overall survival were analyzed. Surgery-induced changes in the peritumoral network connectedness were evaluated in 7 patients with follow-up data. RESULTS: Mean degree centrality was significantly higher in the lesional compared to the contralesional network (P = .032), indicating a tumor-induced effect on its local environment and reflecting high peritumoral network connectedness. Glioblastomas with a neural high epigenetic signature exhibited increased peritumoral network connectedness (P = .010), which was associated with decreased survival (P = .036). Postoperative peritumoral network connectedness tended to decrease, suggesting that surgical resection disrupts the functional communication between the tumor and its peritumoral environment. CONCLUSIONS: The role of network features in predicting patient survival suggests their clinical relevance as imaging biomarkers for assessing personalized treatment strategies, which may include targeting crucial nodes for disconnection or even neuromodulation of neural circuits.

Authors 15

1. Kerstin Jütten corresponding Aachen Department of Neurosurgery

   RWTH Aachen University

   Affiliation as printed

   Department of Neurosurgery, RWTH Aachen University , Aachen ,

   Department of Neurosurgery, RWTH Aachen University , Aachen,

2. Jonas Ort Aachen Department of Neurosurgery

   RWTH Aachen University

   Affiliation as printed

   Department of Neurosurgery, RWTH Aachen University , Aachen ,

   Department of Neurosurgery, RWTH Aachen University , Aachen,

3. Julius M. Kernbach Aachen Department of Neurosurgery

   RWTH Aachen University · University Hospital Heidelberg

   Affiliation as printed

   Department of Neuroradiology, University Hospital Heidelberg , Heidelberg ,

   Department of Neurosurgery, RWTH Aachen University , Aachen ,

   Department of Neuroradiology, University Hospital Heidelberg , Heidelberg,

   Department of Neurosurgery, RWTH Aachen University , Aachen,

4. Anke Meyer‐Baese

   Florida State University · Florida A&M University - Florida State University College of Engineering · Florida Agricultural and Mechanical University

   Affiliation as printed

   Department of Electrical and Computer Engineering, FAMU-FSU College of Engineering , Tallahassee, FL ,

   Department of Electrical and Computer Engineering, FAMU-FSU College of Engineering, Tallahassee , Florida,

5. Uwe H. Meyer-Baese

   Florida State University · Florida A&M University - Florida State University College of Engineering · Florida Agricultural and Mechanical University

   Affiliation as printed

   Department of Electrical and Computer Engineering, FAMU-FSU College of Engineering , Tallahassee, FL ,

   Department of Electrical and Computer Engineering, FAMU-FSU College of Engineering, Tallahassee , Florida,

6. Hussam Aldin Hamou Aachen Department of Neurosurgery

   RWTH Aachen University

   Affiliation as printed

   Department of Neurosurgery, RWTH Aachen University , Aachen ,

   Department of Neurosurgery, RWTH Aachen University , Aachen,

7. Hans Clusmann Aachen Department of Neurosurgery

   RWTH Aachen University

   Affiliation as printed

   Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD) ,

   Department of Neurosurgery, RWTH Aachen University , Aachen ,

   Department of Neurosurgery, RWTH Aachen University , Aachen,

8. Martin Wiesmann Aachen Department of Diagnostic and Interventional Neuroradiology

   RWTH Aachen University

   Affiliation as printed

   Department of Diagnostic and Interventional Neuroradiology, RWTH Aachen University , Aachen ,

   Department of Diagnostic and Interventional Neuroradiology, RWTH Aachen University , Aachen,

9. Juliane Bremer Aachen Institute of Neuropathology

   RWTH Aachen University

   Affiliation as printed

   Institute of Neuropathology, RWTH Aachen University , Aachen ,

   Institute of Neuropathology, RWTH Aachen University , Aachen,

10. Henner Koch Aachen Department of Neurology Section of Epileptology

    RWTH Aachen University

    Affiliation as printed

    Department of Neurology, Section of Epileptology, RWTH Aachen University , Aachen ,

    Department of Neurology, Section of Epileptology, RWTH Aachen University , Aachen,

11. Aniella Bak Aachen Department of Neurology Section of Epileptology

    RWTH Aachen University

    Affiliation as printed

    Department of Neurology, Section of Epileptology, RWTH Aachen University , Aachen ,

    Department of Neurology, Section of Epileptology, RWTH Aachen University , Aachen,

12. Franz Lennard Ricklefs

    University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    Department of Neurosurgery, University Medical Center Hamburg-Eppendorf , Hamburg ,

    Department of Neurosurgery, University Medical Center Hamburg-Eppendorf , Hamburg,

13. Richard Drexler

    Stanford University · University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    Department of Neurology and Neurology Sciences, Stanford University , Stanford, CA ,

    Department of Neurosurgery, University Medical Center Hamburg-Eppendorf , Hamburg ,

    Department of Neurology and Neurology Sciences, Stanford University, Stanford , CA,

    Department of Neurosurgery, University Medical Center Hamburg-Eppendorf , Hamburg,

14. Dieter-Henrik Heiland

    Northwestern University · Friedrich-Alexander-Universität Erlangen-Nürnberg · Universitätsklinikum Erlangen

    Affiliation as printed

    Department of Neurological Surgery, Northwestern University Feinberg School of Medicine , Chicago, IL ,

    Department of Neurosurgery, University Hospital Erlangen, Friedrich-Alexander University Erlangen Nürnberg , Erlangen ,

    Department of Translational Neurosurgery, Friedrich-Alexander University Erlangen-Nürnberg , Erlangen ,

    Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago , IL,

    Department of Neurosurgery, University Hospital Erlangen, Friedrich-Alexander University Erlangen Nürnberg , Erlangen,

    Department of Translational Neurosurgery, Friedrich-Alexander University Erlangen-Nürnberg , Erlangen,

15. Daniel Delev Aachen Department of Neurosurgery

    RWTH Aachen University · Friedrich-Alexander-Universität Erlangen-Nürnberg · Universitätsklinikum Erlangen

    Affiliation as printed

    Department of Neurosurgery, RWTH Aachen University , Aachen ,

    Department of Neurosurgery, University Hospital Erlangen, Friedrich-Alexander University Erlangen Nürnberg , Erlangen ,

    Department of Neurosurgery, RWTH Aachen University , Aachen,

    Department of Neurosurgery, University Hospital Erlangen, Friedrich-Alexander University Erlangen Nürnberg , Erlangen,