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

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Methylation subgroup and molecular heterogeneity is a hallmark of glioblastoma: implications for biopsy targeting, classification and therapy. / Gempt, J; Withake, F; Aftahy, A K; Meyer, H S; Barz, M; Delbridge, C; Liesche-Starnecker, F; Prokop, G; Pfarr, N; Schlegel, J; Meyer, B; Zimmer, C; Menze, B H; Wiestler, B.

In: ESMO OPEN, Vol. 7, No. 5, 10.2022, p. 100566.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Gempt, J, Withake, F, Aftahy, AK, Meyer, HS, Barz, M, Delbridge, C, Liesche-Starnecker, F, Prokop, G, Pfarr, N, Schlegel, J, Meyer, B, Zimmer, C, Menze, BH & Wiestler, B 2022, 'Methylation subgroup and molecular heterogeneity is a hallmark of glioblastoma: implications for biopsy targeting, classification and therapy', ESMO OPEN, vol. 7, no. 5, pp. 100566. https://doi.org/10.1016/j.esmoop.2022.100566

APA

Gempt, J., Withake, F., Aftahy, A. K., Meyer, H. S., Barz, M., Delbridge, C., Liesche-Starnecker, F., Prokop, G., Pfarr, N., Schlegel, J., Meyer, B., Zimmer, C., Menze, B. H., & Wiestler, B. (2022). Methylation subgroup and molecular heterogeneity is a hallmark of glioblastoma: implications for biopsy targeting, classification and therapy. ESMO OPEN, 7(5), 100566. https://doi.org/10.1016/j.esmoop.2022.100566

Vancouver

Gempt J, Withake F, Aftahy AK, Meyer HS, Barz M, Delbridge C et al. Methylation subgroup and molecular heterogeneity is a hallmark of glioblastoma: implications for biopsy targeting, classification and therapy. ESMO OPEN. 2022 Oct;7(5):100566. https://doi.org/10.1016/j.esmoop.2022.100566

Bibtex

@article{ac5e187a3f7d451bae27e54bb6632223,
title = "Methylation subgroup and molecular heterogeneity is a hallmark of glioblastoma: implications for biopsy targeting, classification and therapy",
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 = "Humans, Glioblastoma/genetics, DNA Modification Methylases/genetics, DNA Repair Enzymes/genetics, DNA Copy Number Variations, Brain Neoplasms/genetics, Prospective Studies, Phylogeny, DNA Methylation, Biopsy, ErbB Receptors",
author = "J Gempt and F Withake and Aftahy, {A K} and Meyer, {H S} and M Barz and C Delbridge and F Liesche-Starnecker and G Prokop and N Pfarr and J Schlegel and B Meyer and C Zimmer and Menze, {B H} and B Wiestler",
note = "Copyright {\textcopyright} 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.",
year = "2022",
month = oct,
doi = "10.1016/j.esmoop.2022.100566",
language = "English",
volume = "7",
pages = "100566",
journal = "ESMO OPEN",
issn = "2059-7029",
publisher = "BMJ PUBLISHING GROUP",
number = "5",

}

RIS

TY - JOUR

T1 - Methylation subgroup and molecular heterogeneity is a hallmark of glioblastoma: implications for biopsy targeting, classification and therapy

AU - Gempt, J

AU - Withake, F

AU - Aftahy, A K

AU - Meyer, H S

AU - Barz, M

AU - Delbridge, C

AU - Liesche-Starnecker, F

AU - Prokop, G

AU - Pfarr, N

AU - Schlegel, J

AU - Meyer, B

AU - Zimmer, C

AU - Menze, B H

AU - Wiestler, B

N1 - Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.

PY - 2022/10

Y1 - 2022/10

N2 - 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.

AB - 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.

KW - Humans

KW - Glioblastoma/genetics

KW - DNA Modification Methylases/genetics

KW - DNA Repair Enzymes/genetics

KW - DNA Copy Number Variations

KW - Brain Neoplasms/genetics

KW - Prospective Studies

KW - Phylogeny

KW - DNA Methylation

KW - Biopsy

KW - ErbB Receptors

U2 - 10.1016/j.esmoop.2022.100566

DO - 10.1016/j.esmoop.2022.100566

M3 - SCORING: Journal article

C2 - 36055049

VL - 7

SP - 100566

JO - ESMO OPEN

JF - ESMO OPEN

SN - 2059-7029

IS - 5

ER -