Differences in methylation profiles between long-term survivors and short-term survivors of IDH-wild-type glioblastoma

Matthijs van der Meulen; Ronald C Ramos; Mathew R Voisin; Vikas Patil; Qingxia Wei; Olivia Singh; Seth A Climans; Navya Kalidindi; Rosemarylin Or; Ken Aldape; Phedias Diamandis; David G Munoz; Gelareh Zadeh; Warren P Mason

doi:10.1093/noajnl/vdae001

Differences in methylation profiles between long-term survivors and short-term survivors of IDH-wild-type glioblastoma

Neurooncol Adv. 2024 Jan 12;6(1):vdae001. doi: 10.1093/noajnl/vdae001. eCollection 2024 Jan-Dec.

Authors

Matthijs van der Meulen^{1

2}, Ronald C Ramos^{1

3}, Mathew R Voisin⁴, Vikas Patil⁵, Qingxia Wei⁵, Olivia Singh⁵, Seth A Climans^{1

6}, Navya Kalidindi³, Rosemarylin Or⁷, Ken Aldape⁸, Phedias Diamandis⁹, David G Munoz¹⁰, Gelareh Zadeh^{4

5}, Warren P Mason¹

Affiliations

¹ Department of Medicine, Divisions of Neurology and Medical Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada.
² Department of Neurology, Medisch Spectrum Twente, Enschede, The Netherlands.
³ Division of Neurology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
⁴ Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
⁵ MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
⁶ Department of Oncology, London Regional Cancer Program, London, Ontario, Canada.
⁷ Department of Neurology, The Medical City, Pasig, Philippines.
⁸ Neuro-Oncology Branch, National Cancer Institute, National Institute of Health, Bethesda, Maryland, USA.
⁹ Department of Laboratory Medicine and Pathobiology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
¹⁰ Department of Laboratory Medicine, St. Michaels Hospital, Toronto, Ontario, Canada.

Abstract

Background: Patients with glioblastoma (GBM) have a median overall survival (OS) of approximately 16 months. However, approximately 5% of patients survive >5 years. This study examines the differences in methylation profiles between long-term survivors (>5 years, LTS) and short-term survivors (<1 year, STS) with isocitrate dehydrogenase (IDH)-wild-type GBMs.

Methods: In a multicenter retrospective analysis, we identified 25 LTS with a histologically confirmed GBM. They were age- and sex-matched to an STS. The methylation profiles of all 50 samples were analyzed with EPIC 850k, classified according to the DKFZ methylation classifier, and the methylation profiles of LTS versus STS were compared.

Results: After methylation profiling, 16/25 LTS and 23/25 STS were confirmed to be IDH-wild-type GBMs, all with +7/-10 signature. LTS had significantly increased O6-methylguanine methyltransferase (MGMT) promoter methylation and higher prevalence of FGFR3-TACC3 fusion (P = .03). STS were more likely to exhibit CDKN2A/B loss (P = .01) and higher frequency of NF1 (P = .02) mutation. There were no significant CpGs identified between LTS versus STS at an adjusted P-value of .05. Unadjusted analyses identified key pathways involved in both LTS and STS. The most common pathways were the Hippo signaling pathway and the Wnt pathway in LTS, and GPCR ligand binding and cell-cell signaling in STS.

Conclusions: A small group of patients with IDH-wild-type GBM survive more than 5 years. While there are few differences in the global methylation profiles of LTS compared to STS, our study highlights potential pathways involved in GBMs with a good or poor prognosis.

Keywords: glioblastoma; long-term survivors; methylation; pathway analysis.