Methylation subgroup and molecular heterogeneity is a hallmark of glioblastoma: implications for biopsy targeting, classification and therapy

J Gempt; F Withake; A K Aftahy; H S Meyer; M Barz; C Delbridge; F Liesche-Starnecker; G Prokop; N Pfarr; J Schlegel; B Meyer; C Zimmer; B H Menze; B Wiestler

doi:10.1016/j.esmoop.2022.100566

Methylation subgroup and molecular heterogeneity is a hallmark of glioblastoma: implications for biopsy targeting, classification and therapy

ESMO Open. 2022 Oct;7(5):100566. doi: 10.1016/j.esmoop.2022.100566. Epub 2022 Aug 30.

Authors

J Gempt¹, F Withake², A K Aftahy¹, H S Meyer¹, M Barz¹, C Delbridge³, F Liesche-Starnecker³, G Prokop³, N Pfarr⁴, J Schlegel³, B Meyer¹, C Zimmer², B H Menze⁵, B Wiestler⁶

Affiliations

¹ Department of Neurosurgery, Technical University Munich, Munich, Germany.
² Department of Neuroradiology, Klinikum rechts der Isar, School of Medicine, Technical University Munich, Munich, Germany.
³ Departments of Neuropathology, School of Medicine, Technical University Munich, Munich, Germany.
⁴ Department of Pathology, Institute of Pathology, School of Medicine, Technical University Munich, Munich, Germany.
⁵ Department of Quantitative Biomedicine, University of Zurich, Zurich, Switzerland.
⁶ Department of Neuroradiology, Klinikum rechts der Isar, School of Medicine, Technical University Munich, Munich, Germany; TranslaTUM, Technical University Munich, Munich, Germany. Electronic address: b.wiestler@tum.de.

Abstract

Background: Intratumoral heterogeneity at the cellular and molecular level is a hallmark of glioblastoma (GB) that contributes to treatment resistance and poor clinical outcome. Little is known regarding epigenetic heterogeneity and intratumoral phylogeny and their implication for molecular classification and targeted therapies.

Patients and methods: Multiple tissue biopsies (238 in total) were sampled from 56 newly-diagnosed, treatment-naive GB patients from a prospective in-house cohort and publicly available data and profiled for DNA methylation using the Illumina MethylationEPIC array. Methylation-based classification using the glioma classifier developed by Ceccarelli et al. and estimation of the MGMT promoter methylation status via the MGMT-STP27 model were carried out. In addition, copy number variations (CNVs) and phylogeny were analyzed.

Results: Almost half of the patients (22/56, 39%) harbored tumors composed of heterogeneous methylation subtypes. We found two predominant subtype combinations: classic-/mesenchymal-like, and mesenchymal-/pilocytic astrocytoma-like. Nine patients (16%) had tumors composed of subvolumes with and without MGMT promoter methylation, whereas 20 patients (36%) were homogeneously methylated, and 27 patients (48%) were homogeneously unmethylated. CNV analysis revealed high variations in many genes, including CDKN2A/B, EGFR, and PTEN. Phylogenetic analysis correspondingly showed a general pattern of CDKN2A/B loss and gain of EGFR, PDGFRA, and CDK4 during early stages of tumor development.

Conclusions: (Epi)genetic intratumoral heterogeneity is a hallmark of GB, both at DNA methylation and CNV level. This intratumoral heterogeneity is of utmost importance for molecular classification as well as for defining therapeutic targets in this disease, as single biopsies might underestimate the true molecular diversity in a tumor.

Keywords: glioblastoma; heterogeneity; methylation; phylogeny.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biopsy
Brain Neoplasms* / diagnosis
Brain Neoplasms* / genetics
Brain Neoplasms* / therapy
DNA Copy Number Variations
DNA Methylation
DNA Modification Methylases / genetics
DNA Repair Enzymes / genetics
ErbB Receptors
Glioblastoma* / genetics
Glioblastoma* / therapy
Humans
Phylogeny
Prospective Studies

Substances

DNA Modification Methylases
DNA Repair Enzymes
ErbB Receptors