Temporal change of DNA methylation subclasses between matched newly diagnosed and recurrent glioblastoma

Author:

Drexler RichardORCID,Khatri Robin,Schüller Ulrich,Eckhardt Alicia,Ryba Alice,Sauvigny Thomas,Dührsen Lasse,Mohme Malte,Ricklefs Tammo,Bode Helena,Hausmann Fabian,Huber Tobias B.,Bonn Stefan,Voß Hannah,Neumann Julia E.,Silverbush Dana,Hovestadt Volker,Suvà Mario L.,Lamszus Katrin,Gempt Jens,Westphal Manfred,Heiland Dieter H.,Hänzelmann Sonja,Ricklefs Franz L.

Abstract

AbstractThe longitudinal transition of phenotypes is pivotal in glioblastoma treatment resistance and DNA methylation emerged as an important tool for classifying glioblastoma phenotypes. We aimed to characterize DNA methylation subclass heterogeneity during progression and assess its clinical impact. Matched tissues from 47 glioblastoma patients were subjected to DNA methylation profiling, including CpG-site alterations, tissue and serum deconvolution, mass spectrometry, and immunoassay. Effects of clinical characteristics on temporal changes and outcomes were studied. Among 47 patients, 8 (17.0%) had non-matching classifications at recurrence. In the remaining 39 cases, 28.2% showed dominant DNA methylation subclass transitions, with 72.7% being a mesenchymal subclass. In general, glioblastomas with a subclass transition showed upregulated metabolic processes. Newly diagnosed glioblastomas with mesenchymal transition displayed increased stem cell-like states and decreased immune components at diagnosis and exhibited elevated immune signatures and cytokine levels in serum. In contrast, tissue of recurrent glioblastomas with mesenchymal transition showed increased immune components but decreased stem cell-like states. Survival analyses revealed comparable outcomes for patients with and without subclass transitions. This study demonstrates a temporal heterogeneity of DNA methylation subclasses in 28.2% of glioblastomas, not impacting patient survival. Changes in cell state composition associated with subclass transition may be crucial for recurrent glioblastoma targeted therapies.

Funder

Fördergemeinschaft Kinderkrebs-Zentrum Hamburg

Illumina

HORIZON EUROPE Excellent Science

Deutsche Forschungsgemeinschaft

Universitätsklinikum Hamburg-Eppendorf (UKE)

Publisher

Springer Science and Business Media LLC

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