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

in ESMO open by 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

TLDR

  • The study found that glioblastoma (GB) is a very diverse disease with different types of cells and molecules. The study looked at how these different types of cells and molecules work together to make GB. The study found that almost half of the patients had tumors with different types of cells and molecules. The study also found that some genes and proteins were changed in different parts of the tumor. The study highlights the importance of understanding these differences to better treat GB.

Abstract

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. 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. 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. (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.

Overview

  • The study aims to investigate epigenetic heterogeneity and intratumoral phylogeny in glioblastoma (GB) and their implications for molecular classification and targeted therapies. The study used multiple tissue biopsies from 56 newly-diagnosed, treatment-naive GB patients and profiled them for DNA methylation using the Illumina MethylationEPIC array. Methylation-based classification and estimation of the MGMT promoter methylation status were carried out. In addition, copy number variations (CNVs) and phylogeny were analyzed. The study found that almost half of the patients (22/56, 39%) harbored tumors composed of heterogeneous methylation subtypes. The two predominant subtype combinations were classic-/mesenchymal-like and mesenchymal-/pilocytic astrocytoma-like. The study also revealed high variations in many genes, including CDKN2A/B, EGFR, and PTEN, and a general pattern of CDKN2A/B loss and gain of EGFR, PDGFRA, and CDK4 during early stages of tumor development. The study highlights the importance of epigenetic intratumoral heterogeneity for molecular classification and targeted therapies in GB.

Comparative Analysis & Findings

  • The study compared the outcomes observed under different experimental conditions or interventions detailed in the study. The study found that almost half of the patients (22/56, 39%) harbored tumors composed of heterogeneous methylation subtypes. The two predominant subtype combinations were classic-/mesenchymal-like and mesenchymal-/pilocytic astrocytoma-like. The study also revealed high variations in many genes, including CDKN2A/B, EGFR, and PTEN, and a general pattern of CDKN2A/B loss and gain of EGFR, PDGFRA, and CDK4 during early stages of tumor development. The study highlights the importance of epigenetic intratumoral heterogeneity for molecular classification and targeted therapies in GB.

Implications and Future Directions

  • The study's findings suggest that epigenetic 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. The study also highlights the importance of further research to understand the mechanisms underlying epigenetic intratumoral heterogeneity and its implications for treatment response and clinical outcome in GB. Future research could focus on developing more sensitive and specific biomarkers for molecular classification and targeted therapies in GB, as well as on exploring the role of epigenetic intratumoral heterogeneity in the development and progression of GB.
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