Validation and next-generation update of a DNA methylation-based recurrence predictor for meningioma: a multicenter prospective study

Alexander P Landry; Justin Z Wang; Vikas Patil; Chloe Gui; Mamatjan Yasin; Zeel Patel; Rebecca Yakubov; Ramneet Kaloti; Parnian Habibi; Mark Wilson; Andrew Ajisebutu; Yosef Ellenbogen; Qingxia Wei; Olivia Singh; Julio Sosa; Sheila Mansouri; Christopher Wilson; Aaron A Cohen-Gadol; Piiamaria Virtanen; Noah Burket; Matthew Blackwell; Jenna Koenig; Anthony Alfonso; Joseph Davis; Mohamed A Zaazoue; Ghazaleh Tabatabai; Marcos Tatagiba; Felix Behling; Jill S Barnholtz-Sloan; Andrew E Sloan; Silky Chotai; Lola B Chambless; Alireza Mansouri; Felix Ehret; David Capper; Derek S Tsang; Kenneth Aldape; Andrew Gao; International Consortium on Meningiomas (ICOM); Farshad Nassiri; Gelareh Zadeh

doi:10.1093/neuonc/noae236

Validation and next-generation update of a DNA methylation-based recurrence predictor for meningioma: a multicenter prospective study

Neuro Oncol. 2024 Nov 6:noae236. doi: 10.1093/neuonc/noae236. Online ahead of print.

Authors

Alexander P Landry^{1

2

3}, Justin Z Wang^{1

2

3}, Vikas Patil^{1

3}, Chloe Gui^{1

2

3}, Mamatjan Yasin^{1

3}, Zeel Patel⁴, Rebecca Yakubov^{1

3}, Ramneet Kaloti^{1

3}, Parnian Habibi^{1

3}, Mark Wilson⁴, Andrew Ajisebutu^{1

3}, Yosef Ellenbogen^{1

2

3}, Qingxia Wei^{1

3}, Olivia Singh^{1

3}, Julio Sosa^{1

3}, Sheila Mansouri^{1

3}, Christopher Wilson⁵, Aaron A Cohen-Gadol⁶, Piiamaria Virtanen⁷, Noah Burket⁷, Matthew Blackwell⁷, Jenna Koenig⁷, Anthony Alfonso⁷, Joseph Davis⁷, Mohamed A Zaazoue^{7

8}, Ghazaleh Tabatabai^{9

10

11}, Marcos Tatagiba¹², Felix Behling¹², Jill S Barnholtz-Sloan^{13

14}, Andrew E Sloan¹⁵, Silky Chotai¹⁶, Lola B Chambless¹⁶, Alireza Mansouri¹⁷, Felix Ehret^{18

19}, David Capper^{19

20}, Derek S Tsang²¹, Kenneth Aldape²², Andrew Gao²³; International Consortium on Meningiomas (ICOM); Farshad Nassiri^{1

2

3}, Gelareh Zadeh^{1

2

3}

Affiliations

¹ MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada.
² Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.
³ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
⁴ Temerty School of Medicine, University of Toronto, Toronto, ON, Canada.
⁵ Oklahoma State University College of Osteopathic Medicine, Tulsa, Oklahoma, United States.
⁶ Department of Neurological Surgery, Keck School of Medicine, USC.
⁷ Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN, United States.
⁸ Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, Missouri, United States.
⁹ German Cancer Consortium (DKTK), partner site Tübingen, a partnership between DKFZ and Tübingen University Hospital, Germany.
¹⁰ Cluster of Excellence (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", Eberhard Karls University Tübingen, Tübingen, Germany.
¹¹ Department of Neurology and Interdisciplinary Neuro-Oncology, Center for Neuro-Oncology, Comprehensive Cancer Center, Hertie Institute for Clinical Brain Research, Eberhard Karls University Tübingen, Tübingen, Germany.
¹² Department of Neurosurgery, Center for Neuro-Oncology, Comprehensive Cancer Center, Eberhard Karls University Tübingen, Tübingen, Germany.
¹³ Trans Divisional Research Program (TDRP), Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute, Bethesda, MD, United States.
¹⁴ Center for Biomedical Informatics & Information Technology (CBIIT), National Cancer Institute, Bethesda, MD, United States.
¹⁵ Department of Neurological Surgery & Piedmont Brain Tumor Center, Atlanta, GA.
¹⁶ Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, TN, United States.
¹⁷ Department of Neurosurgery, Penn State Milton S. Hershey Medical Center, Hershey, PA, US.
¹⁸ Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Radiation Oncology, Berlin, Germany.
¹⁹ German Cancer Consortium (DKTK), partner site Berlin, a partnership between DKFZ and Charité - Universitätsmedizin Berlin, Germany.
²⁰ Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropathology, Berlin, Germany.
²¹ Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada.
²² Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
²³ Division of Laboratory Medicine and Pathobiology, University Health Network, Toronto, ON, Canada.

PMID: 39503370
DOI: 10.1093/neuonc/noae236

Abstract

Background: We previously developed a DNA methylation-based risk predictor for meningioma, which has been used locally in a prospective fashion since its original publication. As a follow-up, we validate this model using a large prospective cohort and introduce a streamlined next-generation predictor compatible with newer methylation arrays.

Methods: Genome-wide methylation profiles were generated with the Illumina EPICArray. The performance of our next-generation predictor was compared with our original model and standard-of-care 2021 WHO grade using time-dependent receiver operating characteristic curves. An nomogram was generated by incorporating our methylation predictor with WHO grade and extent of resection.

Results: A total of 1347 meningioma cases were utilized in the study, including 469 prospective cases from 3 institutions and an external cohort of 100 WHO grade 2 cases for model validation. Both the original and next-generation models significantly outperform 2021 WHO grade in predicting early postoperative recurrence. Dichotomizing patients into grade-specific risk subgroups was predictive of outcome within both WHO grades 1 and 2 tumours (p<0.05), while all WHO grade 3 tumours were considered high-risk. Multivariable Cox regression demonstrated benefit of adjuvant radiotherapy in high-risk cases specifically, reinforcing its informative role in clinical decision making. Finally, our next-generation predictor contains nearly 10-fold fewer features than the original model, allowing for targeted arrays.

Conclusions: This next-generation DNA methylation-based meningioma outcome predictor significantly outperforms 2021 WHO grading in predicting time to recurrence. We make this available as a point-and-click tool which will improve prognostication, inform patient selection for RT, and allow for molecularly-stratified clinical trials.

Keywords: DNA methylation; Meningioma; neuro-oncology; outcome prediction; prognosis.